MAPK1c.913G>CUncertain significance

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Variant interpretation report

MAPK1 c.913G>C, p.(Glu305Gln)

NM_002745.4:c.913G>C NP_002736.3:p.(Glu305Gln) View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About MAPK1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 supporting (benign) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 22 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): Variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Total allele frequency = 0.0, meeting the generic ACMG PM2 threshold of <0.1% in all population databases.
BP4 (supporting): Multiple in silico tools predict no deleterious effect: REVEL score 0.334 (below 0.5 pathogenic threshold), BayesDel score -0.039 (within benign range, <0.0), SpliceAI max delta score 0.00 (no predicted splice alteration). The preponderance of computational evidence supports a benign interpretation.

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: 1 Benign evidence criteria: 1

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

Variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Total allele frequency = 0.0, meeting the generic ACMG PM2 threshold of <0.1% in all population databases.

Benign criteria applied · 1

BP4Supporting

BP4 · supporting

Multiple in silico tools predict no deleterious effect: REVEL score 0.334 (below 0.5 pathogenic threshold), BayesDel score -0.039 (within benign range, <0.0), SpliceAI max delta score 0.00 (no predicted splice alteration). The preponderance of computational evidence supports a benign interpretation.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.

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

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

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

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MAPK1 (ERK2), a serine/threonine kinase, is altered by mutation or amplification in various cancer types including head and neck, cervical and ovarian

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

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: 2 met · 12 not met · 5 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

PM2 (Supporting): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (total allele frequency 0.0), meeting the generic ACMG PM2 threshold of <0.1% in all population databases.

BP4 (Supporting Benign): Multiple in silico tools predict no deleterious effect — REVEL score 0.334 (below 0.5 pathogenic threshold), BayesDel score -0.039 (within benign range), and SpliceAI max delta 0.00.

Classification: Variant of Uncertain Significance (VUS). One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) yield indeterminate evidence per the ACMG/AMP 2015 combination rules (PMID:25741868).

Met · 2

PM2 SupportingVariant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Total allele frequency = 0.0, meeting the generic ACMG PM2 threshold of <0.1% in all population databases. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (AF=0)
v4.1 (AF=0)
and gnomAD-Canada v1.0 (AF=0).

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BP4 SupportingMultiple in silico tools predict no deleterious effect: REVEL score 0.334 (below 0.5 pathogenic threshold), BayesDel score -0.039 (within benign range, <0.0), SpliceAI max delta score 0.00 (no predicted splice alteration). The preponderance of computational evidence supports a benign interpretation. Details ▾Hide ▴

Evidence considered

REVEL 0.334 (<0.5)
BayesDel -0.039 (<0.0)
SpliceAI 0.00.

Sources

revelbayesdelspliceai ↗

Not met · 12 · evaluated, threshold not reached

PS2 No de novo data available. No family-based testing, trio analysis, or confirmed maternity/paternity testing identified for this variant. Details ▾Hide ▴

Still missing

No de novo testing or trio analysis available

PS3 No variant-specific functional studies identified. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence for p.(Glu305Gln). Literature review returned no functional assays demonstrating a deleterious effect for this variant. Details ▾Hide ▴

Evidence considered

OncoKB classification: Unknown Oncogenic Effect
no variant-specific reviewed functional evidence.

Still missing

No functional studies available for p.(Glu305Gln)

Sources

oncokb ↗

PS4 No case-control comparison or enrichment data available. The variant is absent from gnomAD, but this alone does not satisfy PS4 without a matched disease cohort demonstrating statistically significant enrichment. Details ▾Hide ▴

Still missing

No case-control or cohort enrichment data

PM1 The variant does not lie within a statistically significant mutational hotspot (CancerHotspots: no hotspot at p.Glu305). No functional domain enrichment data or pathogenic variant cluster is identified at this residue. Details ▾Hide ▴

Evidence considered

CancerHotspots: residue not significant
no hotspot at p.Glu305.

Still missing

No mutational hotspot or functional domain enrichment data

Sources

oncokb ↗

PM6 No de novo observation reported. No patient with confirmed maternity/paternity testing and de novo status identified for this variant. Details ▾Hide ▴

Still missing

No de novo testing data

PP3 Multiple in silico tools do not support a deleterious effect: REVEL score 0.334 (below 0.5 pathogenic threshold), BayesDel score -0.039 (within benign range). SpliceAI max delta score = 0.00 predicts no splice impact. No computational evidence supports pathogenicity. Details ▾Hide ▴

Evidence considered

REVEL 0.334 (<0.5)
BayesDel -0.039 (<0.0)
SpliceAI max delta 0.00.

Sources

revelbayesdelspliceai ↗

PP4 No phenotype specificity data available. No patient or cohort data linking this specific variant to a well-defined clinical phenotype. Details ▾Hide ▴

Still missing

No phenotype data available for variant carriers

PP5 Variant is absent from ClinVar. No reputable source has independently classified this variant as pathogenic, and no expert panel assertion of pathogenicity exists. Details ▾Hide ▴

Evidence considered

ClinVar: no entries
variant not reported by any submitter.

Sources

clinvar ↗

BA1 Allele frequency is 0.0% across all queried gnomAD populations, well below the BA1 threshold of >1%. This criterion requires a high population frequency incompatible with a rare disease variant. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF=0.0
v4.1 AF=0.0 (threshold >1%).

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 Allele frequency is 0.0% across all queried gnomAD populations, well below the BS1 threshold of >0.3%. The variant is too rare in population databases to satisfy this benign criterion. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF=0.0
v4.1 AF=0.0 (threshold >0.3%).

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS3 No functional studies demonstrating a benign effect for this variant. No in vitro or in vivo assays evaluating p.(Glu305Gln) have been identified in the literature. Details ▾Hide ▴

Still missing

No functional studies available for p.(Glu305Gln)

BP6 Variant is absent from ClinVar. No reputable source has independently classified this variant as benign. No expert panel or clinical laboratory assertion of benignity exists. Details ▾Hide ▴

Evidence considered

ClinVar: no entries
variant not reported as benign by any source.

Sources

clinvar ↗

Not assessed · 5 · no assessment recorded

PP1 No segregation data available. No family studies or co-segregation analysis with disease phenotype identified for this variant. Details ▾Hide ▴

Still missing

No segregation or family data available

BS2 No observation in healthy adult controls. No homozygous or hemizygous observations available in population databases to assess against a fully penetrant dominant model. Details ▾Hide ▴

Still missing

No healthy control data available

BS4 No segregation data available showing lack of co-segregation with disease. No family studies have been identified for this variant. Details ▾Hide ▴

Still missing

No segregation or family data available

BP2 No observation in trans with a known pathogenic variant in a dominantly inherited gene. No phase data or co-occurrence data available. Details ▾Hide ▴

Still missing

No phase or co-occurrence data available

PS5 No alternative evidence stream exists for this variant; it is absent from ClinVar and no published functional or case data are available to support an independent assertion of pathogenicity. Details ▾Hide ▴

Still missing

No alternative evidence stream available

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

PVS1 N/AMissense variant p.(Glu305Gln) at c.913; does not fall into PVS1 null-variant buckets (nonsense, frameshift, canonical ±1,2 splice). Generic PVS1 framework (PMC6185798) is not applicable to missense variants. Details ▾Hide ▴

Evidence considered

Variant class: missense substitution p.(Glu305Gln)
not a null variant eligible for PVS1 under the ClinGen SVI PVS1 decision tree (PMC6185798).

Sources

pvs1_generic_framework ↗pvs1_variant_assessment

PS1 N/ANo known pathogenic variant with the same amino acid change (p.Glu305Gln) has been reported in ClinVar or identified in the literature. The variant is absent from all queried sources, so no same-change comparator exists. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar
no prior classification with same amino acid change available.

Sources

clinvar ↗

PM3 N/ANo observation in trans with a pathogenic variant; recessive inheritance data not available for MAPK1. PM3 is reserved for recessive disorders. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AMissense substitution; PM4 applies to non-repeat in-frame deletions/insertions and stop-loss variants altering protein length. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo same-residue (p.Glu305) comparator missense variant with an established pathogenic classification could be identified. PM5 candidate harvesting returned zero eligible comparators. Details ▾Hide ▴

Evidence considered

PM5 candidate search returned zero same-residue pathogenic comparators at p.Glu305.

Sources

pm5_candidatesclinvar ↗

PP2 N/AHCI prior data not available for MAPK1; missense constraint (Z-score) cannot be evaluated. The gene lacks established missense intolerance metrics required for PP2 adjudication. Details ▾Hide ▴

Evidence considered

HCI prior: gene not supported
no missense constraint metrics available.

BP1 N/ANo other missense variant at the same residue (p.Glu305) with an established pathogenic classification is available for comparison. BP1 requires a known pathogenic missense at the same amino acid position. Details ▾Hide ▴

Evidence considered

No pathogenic missense comparator identified at p.Glu305.

Sources

pm5_candidates

BP3 N/AMissense substitution; BP3 applies to in-frame insertions/deletions in repetitive regions without a known function. Details ▾Hide ▴

No further detail was recorded.

BP5 N/ANo case with an alternative molecular basis for disease has been identified. BP5 requires observation of the variant in a case with an alternative clearly pathogenic cause of disease. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AMissense substitution c.913G>C (p.Glu305Gln); BP7 applies exclusively to synonymous (silent) variants predicted to have no splice impact. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: MAPK1
Transcript: NM_002745.4
Coding (HGVS c.): NM_002745.4:c.913G>C
Protein (HGVS p.): NP_002736.3:p.(Glu305Gln)
GRCh38: chr22:21772926 C>G
GRCh37: chr22:22127215 C>G

Gene diagram

Every interpreted variant in MAPK1, mapped onto the exon structure of NM_002745.4. Select a row to find it on the plot.

MAPK1NM_002745.4

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 MAPK1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.010

Pangolin splice gain

0.010

Other predictors

REVEL: 0.334
BayesDel: -0.039

How the predictions were used

Evidence considered

REVEL 0.334 (<0.5)
BayesDel -0.039 (<0.0)
SpliceAI 0.00.

Sources

revelbayesdelspliceai ↗

Evidence considered

REVEL 0.334 (<0.5)
BayesDel -0.039 (<0.0)
SpliceAI max delta 0.00.

Sources

revelbayesdelspliceai ↗

BP7 N/AMissense substitution c.913G>C (p.Glu305Gln); BP7 applies exclusively to synonymous (silent) variants predicted to have no splice impact. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.334. BayesDel score = -0.0393339.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

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

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar Captured ClinVar source record 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.334. BayesDel score = -0.0393339.

Functional

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.