Is MAPK3 p.Glu331Gln (c.991G>C) pathogenic?

MAPK3 p.Glu331Gln (c.991G>C) is classified Uncertain significance in MAPK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-11). AlphaMissense: likely benign (0.1348); Ultra-rare (popmax 0.0261%, nfe).

How common is MAPK3 p.Glu331Gln (c.991G>C) in the general population?

MAPK3 p.Glu331Gln (c.991G>C) is ultra-rare (popmax 0.0261%, nfe) (gnomAD).

What do computational predictors say about MAPK3 p.Glu331Gln (c.991G>C)?

AlphaMissense predicts likely benign (score 0.1348) — an in-silico prediction, not a clinical call.

MAPK3 p.Glu331Gln

c.991G>C · rs202207118 · VCV2204126

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1348 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0261%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1348	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -7.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.86, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 604 bp · p 0.042 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0261% European (non-Finnish) · 308/1,179,940 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0228%

Overall 0.0194% 313/1,613,800 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0261%	3,831
Remaining individualsnot grpmax-eligible	0.0048%	20,823
African / African-American	0.00267%	37,447

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MAPK3
Protein: p.Glu331Gln
Coding: c.991G>C
MANE Select: NM_002746
dbSNP: rs202207118
Type: single nucleotide variant
Location: chr16:30116920 (GRCh38)
Gene constraint: LOEUF 0.935 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.09 · 8 PDB
Residue 331: a turn

Full MAPK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPK3 p.Gly11= Likely benign ★★ same type
MAPK3 p.Pro336= Benign/Likely benign ★★ same type
MAPK3 p.Tyr148Cys Likely pathogenic ★ same type
MAPK3 p.Ala378Asp Uncertain significance ★ ⚠ same type
MAPK3 p.Arg15Ser Uncertain significance ★ ⚠ same type
MAPK3 p.Arg242Gln Uncertain significance ★ ⚠ same type
MAPK3 p.Arg309Gln Uncertain significance ★ ⚠ same type
MAPK3 p.Arg309Gly Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mapk3-p-glu331gln (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown