STAG2c.1018-1G>APathogenic

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Variant interpretation report

STAG2 c.1018-1G>A, p.?

NM_001042749.1:c.1018-1G>A NP_001036214.1:p.? 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 STAG2

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 1 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 1 Pathogenic
Pipeline record: 14 Jul 2026 · version 7.0.3

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): NM_001042749.1:c.1018-1G>A is a canonical splice acceptor variant (c.1018-1G>A, intron 11) predicted to disrupt normal splicing with SpliceAI delta score 1.00 (acceptor loss 1.0). Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants are eligible for PVS1 at very strong strength when loss of function is an established disease mechanism for the gene. STAG2 germline LoF mechanism is supported by targeted literature review identifying multiple publications linking STAG2 loss of function to human disease.
PM2 (moderate): This variant is completely absent from gnomAD v2.1 and v4.1 (0/506,187 alleles across all populations). Allele frequency of 0% is well below the 0.1% PM2 threshold in all subpopulations, including the highest-observed African/African American population (0/30,346 alleles).
PP5 (supporting): This variant has been reported as Pathogenic in ClinVar (Variation ID: 3339587) by Women's Health and Genetics/Laboratory Corporation of America, LabCorp (SCV005204398), a reputable clinical diagnostic laboratory. Although the submission is from a single submitter with criteria provided, the classification from a CLIA-certified laboratory constitutes a reputable source report under ACMG/AMP PP5.

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: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PVS1Very strong

PVS1 · very strong

NM_001042749.1:c.1018-1G>A is a canonical splice acceptor variant (c.1018-1G>A, intron 11) predicted to disrupt normal splicing with SpliceAI delta score 1.00 (acceptor loss 1.0). Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants are eligible for PVS1 at very strong strength when loss of function is an established disease mechanism for the gene. STAG2 germline LoF mechanism is supported by targeted literature review identifying multiple publications linking STAG2 loss of function to human disease.

PM2Moderate

PM2 · moderate

This variant is completely absent from gnomAD v2.1 and v4.1 (0/506,187 alleles across all populations). Allele frequency of 0% is well below the 0.1% PM2 threshold in all subpopulations, including the highest-observed African/African American population (0/30,346 alleles).

PP5Supporting

PP5 · supporting

This variant has been reported as Pathogenic in ClinVar (Variation ID: 3339587) by Women's Health and Genetics/Laboratory Corporation of America, LabCorp (SCV005204398), a reputable clinical diagnostic laboratory. Although the submission is from a single submitter with criteria provided, the classification from a CLIA-certified laboratory constitutes a reputable source report under ACMG/AMP PP5.

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: PVS1 very strong, PM2 moderate, PP5 supporting; combination = 1 very strong + 1 moderate + 1 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

0 / 506,187 alleles

gnomAD v4.1: 0 / 506,187 alleles. Recorded AF 0. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

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

SpliceAI score

1.000 maximum delta

Recorded SpliceAI maximum delta score: 1.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

1 reported laboratory submissions

1 Pathogenic. ClinVar API review status: criteria provided, single submitter.

Applied · PP5 → ClinVar ↗

No screenshot for this evidence

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗

Somatic evidence

1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV54364244, n = 1 times).

Context only COSMIC ↗

For specialists

Technical detail

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

27 criteria with recorded statuses: 3 met · 7 not met · 10 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 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

NM_001042749.1:c.1018-1G>A is a canonical splice acceptor variant in STAG2, where loss of function is a known disease mechanism. The variant is assigned PVS1 at very strong strength under ClinGen SVI PVS1 recommendations (PMC6185798), supported by SpliceAI delta 1.00 predicting abolition of the canonical 3' acceptor site.

This variant is completely absent from gnomAD v2.1 and v4.1 (0/506,187 alleles across all populations), meeting PM2 at moderate strength.

The variant has been reported as Pathogenic in ClinVar (Variation ID: 3339587) by a reputable clinical diagnostic laboratory (LabCorp, SCV005204398), meeting PP5 at supporting strength.

No variant-specific functional data, de novo observations, segregation data, or case-control prevalence data were identified in any reviewed publication. All six ClinVar-cited PMIDs discuss STAG2 and cohesin mutations at the gene level in myeloid malignancies without mentioning NM_001042749.1:c.1018-1G>A.

The combination of 1 very strong (PVS1), 1 moderate (PM2), and 1 supporting (PP5) criterion meets the generic ACMG/AMP 2015 threshold for Pathogenic classification under the rule: 1 Very Strong + 1 Moderate + ≥1 Supporting.

Met · 3

PVS1 Very strongNM_001042749.1:c.1018-1G>A is a canonical splice acceptor variant (c.1018-1G>A, intron 11) predicted to disrupt normal splicing with SpliceAI delta score 1.00 (acceptor loss 1.0). Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants are eligible for PVS1 at very strong strength when loss of function is an established disease mechanism for the gene. STAG2 germline LoF mechanism is supported by targeted literature review identifying multiple publications linking STAG2 loss of function to human disease. Details ▾Hide ▴

Evidence considered

Canonical splice acceptor variant at intron 11 (c.1018-1G>A)
SpliceAI max delta 1.00 (DS_AL=1.0
DS_AG=0.8)
STAG2 loss-of-function mechanism supported by germline disease literature
ClinGen SVI PVS1 framework (PMC6185798) applied

Still missing

Confirm NM_001042749.1 is the clinically relevant transcript
Verify that predicted truncation does not escape NMD
Confirm affected exon is not enriched for population LoF variation

Sources

pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗spliceai ↗

PM2 ModerateThis variant is completely absent from gnomAD v2.1 and v4.1 (0/506,187 alleles across all populations). Allele frequency of 0% is well below the 0.1% PM2 threshold in all subpopulations, including the highest-observed African/African American population (0/30,346 alleles). Details ▾Hide ▴

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: 0/506
187 total alleles (AF=0.0)
gnomAD-Canada v1.0: absent

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PP5 SupportingThis variant has been reported as Pathogenic in ClinVar (Variation ID: 3339587) by Women's Health and Genetics/Laboratory Corporation of America, LabCorp (SCV005204398), a reputable clinical diagnostic laboratory. Although the submission is from a single submitter with criteria provided, the classification from a CLIA-certified laboratory constitutes a reputable source report under ACMG/AMP PP5. Details ▾Hide ▴

Evidence considered

ClinVar Variation ID 3339587
classified as Pathogenic
Submitter: LabCorp (SCV005204398)
clinical testing
germline origin

Still missing

Single submitter only
no expert panel review available

Sources

clinvar ↗

Not met · 7 · evaluated, threshold not reached

PS3 No variant-specific functional data identified. All six ClinVar-cited publications discuss STAG2 and cohesin complex mutations at the gene level in myeloid malignancies; none directly tested or reported functional data for NM_001042749.1:c.1018-1G>A. The ClinVar submitter themselves noted that functional studies have yet to be confirmed. Details ▾Hide ▴

Evidence considered

No variant-specific functional assays found in any reviewed publication
ClinVar submitter noted functional predictions await experimental confirmation

Still missing

No functional studies testing this specific variant exist in the available literature

PM1 No mutational hotspot at this position. The variant is a splice site disruption (c.1018-1G>A) and does not reside within a characterized functional domain residue. No residue-specific hotspot was identified in cancerhotspots.org, and no domain-level clustering of pathogenic variants was established for this specific splice junction. Details ▾Hide ▴

Evidence considered

Not a residue-specific mutational hotspot
No domain-level pathogenic variant clustering at this splice junction

BA1 Allele frequency is 0% in gnomAD v4.1 (0/506,187 alleles), far below the 1% BA1 threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF = 0.0 (0/506
187 alleles)

Sources

gnomad_v4 ↗

BS1 Allele frequency is 0% in gnomAD v4.1, far below the 0.3% BS1 threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF = 0.0 (0/506
187 alleles)

Sources

gnomad_v4 ↗

BP4 Multiple lines of computational evidence predict a deleterious effect. SpliceAI predicts strong splice disruption (max delta 1.00; acceptor loss 1.0, acceptor gain 0.8). BayesDel score is 0.297619, which is below commonly used deleterious thresholds for missense variants but not directly informative for splice variants. Computational evidence does not support a benign interpretation. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 1.00 predicts strong splice disruption
BayesDel 0.297619 (not informative for splicing)

Sources

spliceai ↗bayesdel

BP6 ClinVar reports this variant as Pathogenic (Variation ID: 3339587), not as benign. BP6 requires a reputable source reporting the variant as benign or likely benign. Details ▾Hide ▴

Evidence considered

ClinVar classification: Pathogenic (not benign)

Sources

clinvar ↗

BP7 This is a canonical splice acceptor variant (c.1018-1G>A) with SpliceAI max delta 1.00, predicting strong splice disruption. The variant directly alters a consensus splice site, which is the opposite of the BP7 requirement for a silent intronic variant with no predicted splice impact. Details ▾Hide ▴

Evidence considered

Canonical splice acceptor variant (c.1018-1G>A)
SpliceAI max delta 1.00 predicts strong splice disruption

Sources

spliceai ↗

Not assessed · 10 · no assessment recorded

PS2 No de novo data available for this variant in any reviewed source. Details ▾Hide ▴

Still missing

De novo testing data not available

PS4 Insufficient variant-specific prevalence data in affected individuals. The variant is reported once in ClinVar (single submitter) and once somatically in COSMIC; no case-control or cohort prevalence data are available. Details ▾Hide ▴

Still missing

No case-control studies or cohort prevalence data for this specific variant

PM6 No de novo data available for this variant in any reviewed source. Details ▾Hide ▴

Still missing

No de novo testing data available

PP1 No cosegregation data available for this variant. Details ▾Hide ▴

Still missing

No family segregation data available

PP4 No variant-specific phenotype or family history data available. The variant is listed under STAG2-Related Disorders in ClinVar without specific phenotypic detail. Details ▾Hide ▴

Still missing

No detailed phenotypic information available for this variant

Sources

clinvar ↗

BS2 No data on observation of this variant in healthy adult individuals available. Details ▾Hide ▴

Still missing

No healthy adult observation data available

BS3 No functional studies demonstrating a benign or neutral effect for this variant exist in the available literature. The six ClinVar-cited publications provide only gene-level context without variant-specific functional data. Details ▾Hide ▴

Still missing

No functional studies testing this specific variant

BS4 No cosegregation data available to assess lack of segregation with disease. Details ▾Hide ▴

Still missing

No family segregation data available

BP2 No data on observation of this variant in trans with a known pathogenic variant. Details ▾Hide ▴

Still missing

No trans-configuration data available

BP5 No data on an alternate molecular cause for the phenotype in a case harboring this variant. Details ▾Hide ▴

Still missing

No alternate molecular cause data available

Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/ASplice variant with no amino acid change; no same-amino-acid-change comparator applicable. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AUnable to resolve missense residue context from the normalized protein consequence (NP_001036214.1:p.?). No same-residue comparator variants could be identified for PM5 evaluation. Details ▾Hide ▴

Sources

pm5_candidates

PP2 N/ASplice variant, not a missense change. PP2 applies only to missense variants in genes with a low rate of benign missense variation. Details ▾Hide ▴

No further detail was recorded.

PP3 N/APer ClinGen SVI PVS1 recommendations (PMC6185798), splice prediction evidence (SpliceAI delta 1.00) should not be double-counted with PVS1 for canonical splice variants. The deleterious splice prediction is already captured by PVS1 at very strong strength. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 1.00 (DS_AL=1.0
DS_AG=0.8) supports PVS1 splice mechanism
Double-counting explicitly cautioned against by PMC6185798 framework

Sources

pvs1_variant_assessmentspliceai ↗

BP1 N/ASplice variant, not a missense variant. BP1 applies only to missense variants in genes where a truncating mechanism is primarily causative. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ASkipped per user directive: splice variant, not an in-frame indel in a repetitive region. Details ▾Hide ▴

No further detail was recorded.

PS5 N/ASplice variant; no missense comparator applicable at the same position. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: STAG2
Transcript: NM_001042749.1
Coding (HGVS c.): NM_001042749.1:c.1018-1G>A
Protein (HGVS p.): NP_001036214.1:p.?
GRCh38: chrX:124051120 G>A
GRCh37: chrX:123184970 G>A
ClinVar: 3339587
COSMIC: COSV54364244

Gene diagram

Every interpreted variant in STAG2, mapped onto the exon structure of NM_001042749.1. Select a row to find it on the plot.

STAG2NM_001042749.1

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 STAG2 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 0 / 506,187 alleles AF 0 · 0 homozygotes

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 506,187 alleles · 0 hom

No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/506187 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/30346 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +1 bp

1.000

SpliceAI acceptor gainat +5 bp

0.800

SpliceAI donor lossat +278 bp

0.000

SpliceAI donor gainat -115 bp

0.000

Pangolin splice lossmagnitude shown

-0.900

Pangolin splice gain

0.840

Other predictors

REVEL: Not available
BayesDel: 0.298

How the predictions were used

Evidence considered

SpliceAI max delta 1.00 predicts strong splice disruption
BayesDel 0.297619 (not informative for splicing)

Sources

spliceai ↗bayesdel

Evidence considered

Canonical splice acceptor variant (c.1018-1G>A)
SpliceAI max delta 1.00 predicts strong splice disruption

Sources

spliceai ↗

Evidence considered

SpliceAI max delta 1.00 (DS_AL=1.0
DS_AG=0.8) supports PVS1 splice mechanism
Double-counting explicitly cautioned against by PMC6185798 framework

Sources

pvs1_variant_assessmentspliceai ↗

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 1.00). BayesDel score = 0.297619.

6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients.

Kihara R et al. · 2014

This study comprehensively analyzed mutations in 51 genes in 197 adult de novo AML patients. STAG2 mutations were identified among cohesin complex genes, but individual variant-level details are not provided in the full text. NM_001042749.1:c.1018-1G>A was not identified in this paper.
Does not name this variant
PMID 24487413 ↗
Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms.

Mullenders J et al. · 2015

This study investigated cohesin loss in adult hematopoietic stem cells using shRNA mouse models targeting Stag2 and other cohesin components. The paper demonstrates that cohesin loss leads to myeloproliferative neoplasms but does not evaluate specific human STAG2 variants. NM_001042749.1:c.1018-1G>A was not identified in this paper.
Does not name this variant
PMID 26438359 ↗
Genomic Classification and Prognosis in Acute Myeloid Leukemia.

Papaemmanuil E et al. · 2016

This large-scale study of 1540 AML patients identified 5234 driver mutations across 76 genes. STAG2 is listed among frequently mutated genes and as a class-defining gene in the chromatin-spliceosome AML subgroup. Individual variant-level data including NM_001042749.1:c.1018-1G>A are not reported in the retrieved text.
Does not name this variant
PMID 27276561 ↗
Landscape of genetic lesions in 944 patients with myelodysplastic syndromes.

Haferlach T et al. · 2014

This study screened 104 genes by targeted deep sequencing in 944 patients with MDS. STAG2 is among the genes analyzed, but individual variant-level results are not reported. NM_001042749.1:c.1018-1G>A was not identified in this paper.
Does not name this variant
PMID 24220272 ↗
Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications.

Thol F et al. · 2014

This study analyzed mutations in cohesin complex genes (STAG1, STAG2, SMC1A, SMC3, RAD21) in 389 AML patients. STAG2 mutations were found in 5 patients (1.3%), described as two missense, two frameshift, and one nonsense, but specific variant coordinates including NM_001042749.1:c.1018-1G>A are not listed. The full text confirms mutation-level details are relegated to supplementary tables not available in the retrieved text.
Does not name this variant
PMID 24335498 ↗
Genetic alterations of the cohesin complex genes in myeloid malignancies.

Thota S et al. · 2014

This study analyzed cohesin gene mutations (STAG2, RAD21, SMC1A, SMC3) in 1060 patients with myeloid malignancies. The abstract describes the mutational landscape at the gene level without reporting specific variant coordinates. NM_001042749.1:c.1018-1G>A was not identified in the abstract.
Does not name this variant
PMID 25006131 ↗

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

gnomAD v4.1 0 / 506,187 recorded alleles Open source ↗

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

SpliceAI Lookup Recorded maximum delta 1.000 Open source ↗

ClinVar 1 Pathogenic Open source ↗

COSMIC Captured COSMIC 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

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 3339587)

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 1.00). BayesDel score = 0.297619.

Somatic

This variant has previously been reported in somatic cancers (COSMIC; COSV54364244, n = 1 times).