JAK2c.1849G>TPathogenic

Print report

Variant interpretation report

JAK2 c.1849G>T, p.(Val617Phe)

NM_004972.3:c.1849G>T NP_004963.1:p.(Val617Phe) View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About JAK2

No gene-level summary was recorded for this case.

Key facts

Evidence used: 2 strong (pathogenic) · 1 moderate (pathogenic) · 3 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 14 Pathogenic · 5 Likely pathogenic · 1 pathogenic
Pipeline record: 19 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PS3 (strong): Well-established functional studies demonstrate JAK2 V617F is a gain-of-function mutation. James et al. (2005) showed that V617F induces constitutive STAT5 transcriptional activation in luciferase reporter assays, transforms Ba/F3 cells to cytokine-independent growth, and causes erythrocytosis in a mouse bone marrow transplant model. Haan et al. (2009) confirmed constitutive activation of STAT1/3/5, ERK1/2, and p38 pathways, with SOCS-mediated feedback regulation. Sanz et al. (2011) demonstrated altered catalytic activity via peptide microarray. McKenney et al. (2018) confirmed oncogenicity in a Jak2V617F-driven MPN mouse model. Multiple independent studies with diverse functional assays consistently support a gain-of-function pathogenic mechanism.
PS4 (strong): JAK2 V617F is the hallmark mutation in myeloproliferative neoplasms, reported in >80% of polycythemia vera, ~50% of essential thrombocythemia, and ~50% of primary myelofibrosis cases. It is virtually absent from the general germline population — gnomAD v2.1 shows global AF of 0.034% (97/281,626 alleles) with 5 homozygotes, and v4.1 shows 0.029% (471/1,605,918 alleles) with 17 homozygotes, frequencies that almost certainly represent somatic clonal hematopoiesis rather than true germline variation. The extreme case enrichment meets the PS4 threshold at the strong level.
PM1 (moderate): The p.Val617Phe substitution is located in the JH2 pseudokinase domain (amino acids ~545-809), a well-established critical regulatory domain that mediates autoinhibition of JAK2 kinase activity. The JH2 domain is a recognized mutational hotspot for gain-of-function variants in myeloproliferative neoplasms, with multiple activating mutations described at this locus (e.g., K539L, R564Q, E695K). Position 617 is specifically identified as a residue whose alteration disrupts autoinhibitory interactions with the JH1 kinase domain activation loop.
PM2 (supporting): The variant is present at very low frequency in gnomAD population databases: global AF 0.034% in v2.1 and 0.029% in v4.1, both below the 0.1% threshold for PM2. The maximum subpopulation frequency is 0.075% (Ashkenazi Jewish, v4.1). The presence of homozygotes (5 in v2.1, 17 in v4.1) is noted but is consistent with somatic clonal hematopoiesis in aging individuals rather than true germline homozygosity.
PP3 (supporting): REVEL score of 0.881 is above the established deleterious threshold (≥0.75). Multiple in silico predictors support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.01). HCI Prior is not available for JAK2.
PP5 (supporting): ClinVar reports the variant as Pathogenic by 14 clinical laboratories and Likely pathogenic by 5 laboratories (ClinVar variation ID 14662). Multiple reputable clinical diagnostic laboratories have independently classified this variant as pathogenic, supporting a disease-causing role.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 6 Benign evidence criteria: 0

Pathogenic criteria applied · 6

PS3Strong

PS3 · strong

Well-established functional studies demonstrate JAK2 V617F is a gain-of-function mutation. James et al. (2005) showed that V617F induces constitutive STAT5 transcriptional activation in luciferase reporter assays, transforms Ba/F3 cells to cytokine-independent growth, and causes erythrocytosis in a mouse bone marrow transplant model. Haan et al. (2009) confirmed constitutive activation of STAT1/3/5, ERK1/2, and p38 pathways, with SOCS-mediated feedback regulation. Sanz et al. (2011) demonstrated altered catalytic activity via peptide microarray. McKenney et al. (2018) confirmed oncogenicity in a Jak2V617F-driven MPN mouse model. Multiple independent studies with diverse functional assays consistently support a gain-of-function pathogenic mechanism.

PS4Strong

PS4 · strong

JAK2 V617F is the hallmark mutation in myeloproliferative neoplasms, reported in >80% of polycythemia vera, ~50% of essential thrombocythemia, and ~50% of primary myelofibrosis cases. It is virtually absent from the general germline population — gnomAD v2.1 shows global AF of 0.034% (97/281,626 alleles) with 5 homozygotes, and v4.1 shows 0.029% (471/1,605,918 alleles) with 17 homozygotes, frequencies that almost certainly represent somatic clonal hematopoiesis rather than true germline variation. The extreme case enrichment meets the PS4 threshold at the strong level.

PM1Moderate

PM1 · moderate

The p.Val617Phe substitution is located in the JH2 pseudokinase domain (amino acids ~545-809), a well-established critical regulatory domain that mediates autoinhibition of JAK2 kinase activity. The JH2 domain is a recognized mutational hotspot for gain-of-function variants in myeloproliferative neoplasms, with multiple activating mutations described at this locus (e.g., K539L, R564Q, E695K). Position 617 is specifically identified as a residue whose alteration disrupts autoinhibitory interactions with the JH1 kinase domain activation loop.

PM2Supporting

PM2 · supporting

The variant is present at very low frequency in gnomAD population databases: global AF 0.034% in v2.1 and 0.029% in v4.1, both below the 0.1% threshold for PM2. The maximum subpopulation frequency is 0.075% (Ashkenazi Jewish, v4.1). The presence of homozygotes (5 in v2.1, 17 in v4.1) is noted but is consistent with somatic clonal hematopoiesis in aging individuals rather than true germline homozygosity.

PP3Supporting

PP3 · supporting

REVEL score of 0.881 is above the established deleterious threshold (≥0.75). Multiple in silico predictors support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.01). HCI Prior is not available for JAK2.

PP5Supporting

PP5 · supporting

ClinVar reports the variant as Pathogenic by 14 clinical laboratories and Likely pathogenic by 5 laboratories (ClinVar variation ID 14662). Multiple reputable clinical diagnostic laboratories have independently classified this variant as pathogenic, supporting a disease-causing role.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PS4 strong, PM1 moderate, PM2 supporting, PP3 supporting, PP5 supporting; combination = 2 strong + 1 moderate + 3 supporting, which maps to Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

471 / 1,605,918 alleles

gnomAD v4.1: 471 / 1,605,918 alleles. Recorded AF 0.00029329. Recorded homozygote count 17.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000344428; MAF= 0.03444%, 97/281626 alleles, homozygotes = 5) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000579934; MAF= 0.05799%, 6/10346 alleles, homozygotes = 0); grpmax FAF= 0.00030518.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0005979560774081322, 11/18396 alleles, homozygotes = 0).

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

20 reported laboratory submissions

14 Pathogenic · 5 Likely pathogenic · 1 pathogenic.

Applied · PP5 → ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.

Applied · PS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

42916 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV67569051, n = 42916 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 6 met · 4 not met · 9 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

JAK2 c.1849G>T (p.Val617Phe) is the canonical activating mutation in myeloproliferative neoplasms, identified in >80% of polycythemia vera cases and a substantial proportion of essential thrombocythemia and primary myelofibrosis cases.

Well-established functional studies across multiple independent laboratories demonstrate that V617F disrupts JH2 pseudokinase domain autoinhibition, resulting in constitutive JAK2 kinase activity, STAT-mediated transcriptional activation, cytokine-independent cell growth, and erythrocytosis in murine models.

The variant is located in the JH2 pseudokinase domain, a critical regulatory region and established mutational hotspot for gain-of-function variants in myeloproliferative neoplasms.

Population databases show the variant at very low frequency (gnomAD v2.1: 0.034%; v4.1: 0.029%), well below the 0.1% PM2 threshold. Observed homozygotes are consistent with somatic clonal hematopoiesis rather than germline events.

REVEL in silico prediction score of 0.881 supports a deleterious effect on protein function.

ClinVar reports the variant as Pathogenic by 14 clinical diagnostic laboratories and Likely pathogenic by 5, with variation ID 14662.

Two strong pathogenic criteria (PS3 + PS4) satisfy the '2 Strong' pathogenic combination rule under the generic ACMG/AMP 2015 framework. Additional moderate (PM1) and supporting criteria (PM2, PP3, PP5) provide further confirmatory evidence.

Met · 6

PS3 StrongWell-established functional studies demonstrate JAK2 V617F is a gain-of-function mutation. James et al. (2005) showed that V617F induces constitutive STAT5 transcriptional activation in luciferase reporter assays, transforms Ba/F3 cells to cytokine-independent growth, and causes erythrocytosis in a mouse bone marrow transplant model. Haan et al. (2009) confirmed constitutive activation of STAT1/3/5, ERK1/2, and p38 pathways, with SOCS-mediated feedback regulation. Sanz et al. (2011) demonstrated altered catalytic activity via peptide microarray. McKenney et al. (2018) confirmed oncogenicity in a Jak2V617F-driven MPN mouse model. Multiple independent studies with diverse functional assays consistently support a gain-of-function pathogenic mechanism. Details ▾Hide ▴

Evidence considered

Constitutive STAT5 activation in luciferase reporter assay (gamma-2A cells)
Cytokine-independent growth transformation of Ba/F3 and FDCP-EpoR cells
Erythrocytosis induction in murine bone marrow transplant model
Constitutive phosphorylation of STAT1/3/5
ERK1/2
p38
and AKT
SOCS-mediated feedback regulation and ubiquitin-proteasome degradation
Altered catalytic activity confirmed by peptide microarray
Jak2V617F-driven MPN mouse model demonstrates oncogenicity

Sources

PMID:15793561 ↗PMID:19543316 ↗PMID:21533163 ↗PMID:29355841 ↗

PS4 StrongJAK2 V617F is the hallmark mutation in myeloproliferative neoplasms, reported in >80% of polycythemia vera, ~50% of essential thrombocythemia, and ~50% of primary myelofibrosis cases. It is virtually absent from the general germline population — gnomAD v2.1 shows global AF of 0.034% (97/281,626 alleles) with 5 homozygotes, and v4.1 shows 0.029% (471/1,605,918 alleles) with 17 homozygotes, frequencies that almost certainly represent somatic clonal hematopoiesis rather than true germline variation. The extreme case enrichment meets the PS4 threshold at the strong level. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 global AF = 0.034% (97/281
626 alleles
5 homozygotes)
gnomAD v4.1 global AF = 0.029% (471/1
605
918 alleles
17 homozygotes)
Reported in >80% of polycythemia vera patients (James et al. 2005)
ClinVar: Pathogenic by 14 clinical laboratories
Likely pathogenic by 5
COSMIC: 42
916 somatic occurrences

Still missing

Formal case-control odds ratio not calculated — enrichment is well-established in the literature but quantitative OR/CI not derived from case data.

Sources

gnomad_v2 ↗gnomad_v4 ↗clinvar ↗PMID:15793561 ↗

PM1 ModerateThe p.Val617Phe substitution is located in the JH2 pseudokinase domain (amino acids ~545-809), a well-established critical regulatory domain that mediates autoinhibition of JAK2 kinase activity. The JH2 domain is a recognized mutational hotspot for gain-of-function variants in myeloproliferative neoplasms, with multiple activating mutations described at this locus (e.g., K539L, R564Q, E695K). Position 617 is specifically identified as a residue whose alteration disrupts autoinhibitory interactions with the JH1 kinase domain activation loop. Details ▾Hide ▴

Evidence considered

V617F located in JH2 pseudokinase domain — critical autoinhibitory region
JH2 domain is a well-established mutational hotspot in MPN
Multiple lines of evidence show JH2 disruption leads to constitutive kinase activation
Residues 619-670 form one of three inhibitory regions within JH2

Sources

PMID:15793561 ↗PMID:19543316 ↗PMID:21533163 ↗

PM2 SupportingThe variant is present at very low frequency in gnomAD population databases: global AF 0.034% in v2.1 and 0.029% in v4.1, both below the 0.1% threshold for PM2. The maximum subpopulation frequency is 0.075% (Ashkenazi Jewish, v4.1). The presence of homozygotes (5 in v2.1, 17 in v4.1) is noted but is consistent with somatic clonal hematopoiesis in aging individuals rather than true germline homozygosity. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF = 0.034% (<0.1% threshold)
gnomAD v4.1 AF = 0.029% (<0.1% threshold)
Max subpop AF (Ashkenazi Jewish v4.1) = 0.075%
grpmax FAF v2.1 = 0.000305
v4.1 = 0.000277

Still missing

Homozygote counts (5-17) are unusual for a rare germline variant — consistent with somatic clonal hematopoiesis but formal CHIP analysis not performed.

Sources

gnomad_v2 ↗gnomad_v4 ↗

PP3 SupportingREVEL score of 0.881 is above the established deleterious threshold (≥0.75). Multiple in silico predictors support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.01). HCI Prior is not available for JAK2. Details ▾Hide ▴

Evidence considered

REVEL score = 0.881 (threshold ≥0.75 for deleterious)
SpliceAI max delta = 0.01 (no predicted splice impact)
HCI Prior not available for JAK2

Still missing

BayesDel score 0.35869 is below typical thresholds — not used for PP3.

Sources

revelspliceai ↗

PP5 SupportingClinVar reports the variant as Pathogenic by 14 clinical laboratories and Likely pathogenic by 5 laboratories (ClinVar variation ID 14662). Multiple reputable clinical diagnostic laboratories have independently classified this variant as pathogenic, supporting a disease-causing role. Details ▾Hide ▴

Evidence considered

ClinVar classification: Pathogenic (14 clinical laboratories)
ClinVar classification: Likely pathogenic (5 clinical laboratories)
ClinVar classification: pathogenic (1 clinical laboratory)

Still missing

Only 1 of 30 ClinVar submissions provides ACMG criteria — the remainder are asserted without criteria.

Sources

clinvar ↗

Not met · 4 · evaluated, threshold not reached

PS2 No de novo observation with confirmed maternity and paternity is documented for this variant in any source. The literature_pass flags PMID:25741868 for PS2 but this is the ACMG/AMP framework guideline paper, not a de novo case report. Details ▾Hide ▴

Evidence considered

No de novo data in any reviewed source.

Still missing

No de novo observation data available.

BA1 gnomAD global allele frequency is 0.034% (v2.1) and 0.029% (v4.1), far below the 1% threshold for BA1. Maximum subpopulation frequency is 0.075% (Ashkenazi Jewish, v4.1). Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF = 0.034% (threshold >1%)
gnomAD v4.1 AF = 0.029% (threshold >1%)
Max subpop AF = 0.075% (threshold >1%)

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 gnomAD global allele frequency is 0.034% (v2.1) and 0.029% (v4.1), below the 0.3% threshold for BS1. Maximum subpopulation frequency is 0.075% (Ashkenazi Jewish, v4.1), also below the threshold. The variant is not observed at a frequency greater than expected for the disorder. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF = 0.034% (threshold >0.3%)
gnomAD v4.1 AF = 0.029% (threshold >0.3%)
Max subpop AF = 0.075% (threshold >0.3%)

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP4 REVEL score of 0.881 predicts a deleterious effect, contradicting the BP4 requirement that multiple lines of computational evidence suggest no impact on gene product. SpliceAI also shows no splicing impact, but the primary in silico metric (REVEL) strongly supports pathogenicity. Details ▾Hide ▴

Evidence considered

REVEL = 0.881 (deleterious) — contradicts BP4 requirement for benign computational prediction.

Sources

revel

Not assessed · 9 · no assessment recorded

PS1 No alternate nucleotide change at c.1849 resulting in the same amino acid change (p.Val617Phe) has been identified in the case data. Only the G>T transversion is documented. Details ▾Hide ▴

Still missing

No alternate nucleotide substitution at the same codon with established pathogenicity identified.

PP1 No segregation data available. PP1 requires co-segregation with disease in multiple affected family members. Details ▾Hide ▴

Still missing

No family segregation data in case materials.

PP2 Gene-level constraint metrics (Z-score, pLI, missense depletion) for JAK2 are not evaluated in the case materials. PP2 requires a low rate of benign missense variation with missense variants as a common disease mechanism. While JAK2 gain-of-function missense variants are a well-known disease mechanism, formal constraint metric assessment is needed. Details ▾Hide ▴

Still missing

JAK2 gene constraint metrics (gnomAD Z-score
missense o/e) not evaluated.

PP4 Patient phenotype and family history data are not provided in the case materials. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. Details ▾Hide ▴

Still missing

No patient phenotype or family history provided.

BS2 BS2 requires observation of the variant in healthy adults with full penetrance expected at an early age. No such data are available in the case materials. Details ▾Hide ▴

Still missing

No data on observation in healthy adults with expected full penetrance at early age.

BS4 No segregation data available. BS4 requires lack of segregation in affected family members. Details ▾Hide ▴

Still missing

No family segregation data in case materials.

BP2 No phase data available. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant for recessive disorders. Details ▾Hide ▴

Still missing

No trans/cis phase data available.

BP5 No data available regarding an alternate molecular basis for disease in a case harboring this variant. BP5 requires the variant to be found in a case with an alternate molecular basis for disease. Details ▾Hide ▴

Still missing

No data on alternate molecular basis in cases with this variant.

PS5 While ClinVar reports a 'criteria provided, single submitter' classification of Likely pathogenic from Labcorp/Invitae, the full ACMG criteria trail from that submission is not available for independent evaluation. PP5 is applied instead to capture the ClinVar pathogenic consensus. Details ▾Hide ▴

Evidence considered

ClinVar review status: 'criteria provided
single submitter' — limited independent verifiability.

Still missing

ACMG criteria applied by the single criteria-providing submitter (SCV002307245) not accessible for review.

Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/ANM_004972.3:c.1849G>T is a missense substitution (p.Val617Phe), not a null variant (nonsense, frameshift, or canonical splice). The variant does not fall into the default generic PVS1 null-variant buckets defined by ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴

Evidence considered

Missense substitution at c.1849G>T resulting in p.Val617Phe
variant_bucket='other'
apply_generic_pvs1_framework=false per pvs1_variant_assessment.

Sources

pvs1_generic_framework ↗

PM3 N/ASkipped per instruction. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASkipped per instruction. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 candidate harvesting did not identify valid same-residue comparator variants. The pm5_candidates.json indicates eligibility for classic PM5 search could not be confirmed. Details ▾Hide ▴

Evidence considered

pm5_mode='unknown'
eligible_for_classic_pm5_search=false.

PM6 N/ANo de novo observation data available. PM6 requires a de novo observation with confirmed maternity and paternity. Details ▾Hide ▴

No further detail was recorded.

BS3 N/AFunctional evidence consistently demonstrates a gain-of-function pathogenic effect. BS3 requires well-established functional studies showing no deleterious effect — the opposite of what is observed. Details ▾Hide ▴

Evidence considered

All functional studies demonstrate gain-of-function
not benign effect.

BP1 N/AJAK2 disease mechanism is predominantly gain-of-function via activating missense variants, not loss-of-function via truncating variants. BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. Details ▾Hide ▴

Evidence considered

JAK2 pathogenicity is driven by gain-of-function missense variants in the JH2 pseudokinase and JH1 kinase domains.

BP3 N/ASkipped per instruction. Details ▾Hide ▴

No further detail was recorded.

BP6 N/ANo reputable source has classified this variant as benign. ClinVar classifications are exclusively pathogenic or likely pathogenic. Details ▾Hide ▴

Evidence considered

All ClinVar classifications are Pathogenic or Likely pathogenic
no benign assertions found.

BP7 N/ANM_004972.3:c.1849G>T is a missense variant (p.Val617Phe), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

Evidence considered

Missense substitution — BP7 not applicable.

Identifiers

Gene: JAK2
Transcript: NM_004972.3
Coding (HGVS c.): NM_004972.3:c.1849G>T
Protein (HGVS p.): NP_004963.1:p.(Val617Phe)
GRCh38: chr9:5073770 G>T
GRCh37: chr9:5073770 G>T
ClinVar: 14662
COSMIC: COSV67569051

Gene diagram

Every interpreted variant in JAK2, mapped onto the exon structure of NM_004972.3. Select a row to find it on the plot.

JAK2NM_004972.3

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in JAK2 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 471 / 1,605,918 alleles AF 0.000293 · 17 homozygotes · FAF 0.000277

gnomAD v2.1 97 / 281,626 alleles AF 0.000344 · 5 homozygotes · FAF 0.000305

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.00029 · 471 / 1,605,918 alleles · 17 hom · FAF 0.00028

Ashkenazi Jewish22 / 29,488	0.000751 hom
Middle Eastern3 / 6,062	0.00049
European (non-Finnish)356 / 1,173,540	0.000313 hom
European (Finnish)19 / 63,542	0.00032 hom
South Asian27 / 90,798	0.0003
African/African American19 / 74,656	0.000251 hom
Remaining individuals13 / 62,224	0.00021
Admixed American7 / 59,922	0.00012
East Asian5 / 44,774	0.00011

0 alternate alleles recorded in 1 other group: Amish.

gnomAD v2.1

AF 0.00034 · 97 / 281,626 alleles · 5 hom · FAF 0.00031

Ashkenazi Jewish6 / 10,346	0.00058
European (Finnish)14 / 24,872	0.000561 hom
European (non-Finnish)49 / 128,650	0.000383 hom
South Asian10 / 30,490	0.00033
African/African American8 / 24,896	0.000321 hom
Admixed American6 / 35,276	0.00017
East Asian3 / 19,928	0.00015
Remaining individuals1 / 7,168	0.00014

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.00029329; MAF= 0.02933%, 471/1605918 alleles, homozygotes = 17) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000746066; MAF= 0.07461%, 22/29488 alleles, homozygotes = 1); grpmax FAF= 0.0002771.

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0005979560774081322, 11/18396 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -72 bp

0.010

SpliceAI acceptor gainat -59 bp

0.000

SpliceAI donor lossat +15 bp

0.010

SpliceAI donor gainat +19 bp

0.000

Pangolin splice lossmagnitude shown

-0.060

Pangolin splice gain

0.000

Other predictors

REVEL: 0.881
BayesDel: 0.359

How the predictions were used

Evidence considered

REVEL score = 0.881 (threshold ≥0.75 for deleterious)
SpliceAI max delta = 0.01 (no predicted splice impact)
HCI Prior not available for JAK2

Still missing

BayesDel score 0.35869 is below typical thresholds — not used for PP3.

Sources

revelspliceai ↗

Evidence considered

REVEL = 0.881 (deleterious) — contradicts BP4 requirement for benign computational prediction.

Sources

revel

BP7 N/ANM_004972.3:c.1849G>T is a missense variant (p.Val617Phe), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

Evidence considered

Missense substitution — BP7 not applicable.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.881. BayesDel score = 0.35869.

7 paper records listed. 6 cited in the classification.

Cited in the classification

Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.

Baxter EJ et al. · 2005 Mar 19-25

Identified the acquired JAK2 V617F mutation in myeloproliferative disorders. This is one of the original discovery papers for JAK2 V617F, published simultaneously with James et al. (PMID:15793561) and others in 2005.
→ PS4 Names this variant
PMID 15781101 ↗
Source detail

Location Abstract confirms V617F identification in MPN; full text not available for detailed review
A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.

James C et al. · 2005 Apr 28

Identified JAK2 V617F as a clonal, acquired G-to-T transversion at nucleotide 1849 in >80% of polycythaemia vera patients. The mutation confers constitutive STAT5 transcriptional activation in luciferase assays, transforms Ba/F3 and FDCP-EpoR cells to cytokine-independent growth, and induces erythrocytosis (haematocrit 60%) in a murine bone marrow transplant model. Wild-type JAK2 acts as a dominant negative, explaining selection for loss of heterozygosity at 9p.
→ PS3 → PS4 → PM1 Names this variant
PMID 15793561 ↗
Source detail

one G-to-T mutation at nucleotide 1849 (in exon 12) leading to a substitution of valine to phenylalanine at position 617 (V617F)

Location Results p1144-1146; Figure 2a, 2e, 2f; Figure 3a-f; Figure 4

Context STAT5 luciferase reporter assay (gamma-2A cells), Ba/F3-EpoR and FDCP-EpoR cell transformation, murine bone marrow transplant (C57/B6)
A gain-of-function mutation of JAK2 in myeloproliferative disorders.

Kralovics R et al. · 2005 Apr 28

Identified a gain-of-function JAK2 V617F mutation in polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. The study linked V617F to 9p loss of heterozygosity and demonstrated constitutive kinase activity.
→ PS4 Names this variant
PMID 15858187 ↗
Source detail

Location Title confirms V617F; full text not available for detailed review
SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling.

JAK2 V617F, along with T875N and K539L mutants, demonstrated constitutive activation of STAT1/3/5, ERK1/2, and p38 in HEK Flp-In-293 inducible cells. SOCS1 and SOCS3 were transcriptionally induced by V617F and recruited to the plasma membrane, leading to ubiquitin-proteasome-mediated degradation of the mutant protein. Constitutive Jak2-V617F activity is self-limiting through SOCS-mediated feedback, explaining the need for homozygous mutation or gene amplification to achieve full transformation.
→ PS3 Names this variant
PMID 19543316 ↗
Source detail

The genetic mutation results in a valine to phenylalanine substitution in the pseudokinase domain of Jak2 at amino acid position 617, generating a constitutively active protein.

Location Abstract; Results p3070-3074; Figures 1-4

Context HEK Flp-In-293 inducible transfectants (with/without EpoR), HEL cells (homozygous V617F), SET2 cells (heterozygous V617F)
Analysis of Jak2 catalytic function by peptide microarrays: the role of the JH2 domain and V617F mutation.

Peptide microarray analysis of JAK2 catalytic function demonstrated that the V617F mutation in the JH2 pseudokinase domain alters substrate specificity and enhances catalytic activity. The study provides direct biochemical evidence that the JH2 domain negatively regulates JH1 kinase activity and that V617F relieves this autoinhibition, altering the phosphopeptide signature compared to wild-type JAK2.
→ PS3 → PM1 Names this variant
PMID 21533163 ↗
Source detail

Location Title and abstract; full text confirms variant-level analysis

Context Peptide microarray (PamGene) with recombinant JAK2 kinase domains
JAK2/IDH-mutant-driven myeloproliferative neoplasm is sensitive to combined targeted inhibition.

Generated a JAK2/IDH-mutant-driven myeloproliferative neoplasm mouse model expressing Jak2V617F combined with mutant IDH1 or IDH2. The model demonstrated that combined JAK2 and IDH inhibition is effective in targeting MPN progression, confirming the central pathogenic role of Jak2V617F in disease maintenance and progression to bone marrow failure or AML.
→ PS3 Names this variant
PMID 29355841 ↗
Source detail

Location Title and abstract; full text confirms Jak2V617F-driven model

Context Jak2V617F knock-in mouse model combined with mutant IDH1/IDH2; pharmacological inhibition studies

Other recorded publications

The pseudokinase domain is required for suppression of basal activity of Jak2 and Jak3 tyrosine kinases and for cytokine-inducible activation of signal transduction.

Demonstrated that the JH2 pseudokinase domain negatively regulates Jak2 and Jak3 tyrosine kinase activity. Deletion of JH2 resulted in increased tyrosine phosphorylation and downstream signaling. This paper was published in 2002, predating the discovery of JAK2 V617F (2005), and does not mention or study the V617F variant.
Does not name this variant
PMID 12351625 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 471 / 1,605,918 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗

ClinVar 14 Pathogenic · 5 Likely pathogenic · 1 pathogenic Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0005979560774081322, 11/18396 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Pathogenic (14 clinical laboratories) and as Likely pathogenic (5 clinical laboratories) and as pathogenic (1 clinical laboratory). (ClinVarID = 14662)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.881. BayesDel score = 0.35869.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV67569051, n = 42916 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.