Is MAP3K3 p.Val281Met (c.841G>A) pathogenic?

MAP3K3 p.Val281Met (c.841G>A) is classified Benign in MAP3K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-04-16). AlphaMissense: likely benign (0.1182); Low-frequency (popmax 1.24%, eas).

How common is MAP3K3 p.Val281Met (c.841G>A) in the general population?

MAP3K3 p.Val281Met (c.841G>A) is low-frequency (popmax 1.24%, eas) (gnomAD).

What do computational predictors say about MAP3K3 p.Val281Met (c.841G>A)?

AlphaMissense predicts likely benign (score 0.1182) — an in-silico prediction, not a clinical call.

MAP3K3 p.Val281Met

c.841G>A · rs36109904 · VCV713294

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1182 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.24%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1182	likely benign
REVEL	0.172	moderately benign-leaning
SaProt	LLR -7.23	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 12 kb · p 1.9e-20 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.24% East Asian · 555/44,876 alleles

Filtering AF 1.15% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.12%

Overall 0.0492% 794/1,614,020 alleles · low-frequency exomes 658/1,461,762 · genomes 136/152,258 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.24%	81
Remaining individualsnot grpmax-eligible	0.186%	539
South Asian	0.0999%	1,001
Middle Eastern	0.0165%	6,062
Admixed American	0.0117%	8,575
African / African-American	0.008%	12,503
European (non-Finnish)	0.00153%	65,551

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: MAP3K3
Protein: p.Val281Met
Coding: c.841G>A
MANE Select: NM_002401
dbSNP: rs36109904
Type: single nucleotide variant
Location: chr17:63688851 (GRCh38)
Gene constraint: LOEUF 0.209 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.20 · 6 PDB
Residue 281: a UniProt-annotated variant site (in)

Full MAP3K3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K3 p.Ile441Met Pathogenic/Likely pathogenic ★★ same type
MAP3K3 p.His133Tyr Uncertain significance ★★ ⚠ same type
MAP3K3 p.Met524Val Uncertain significance ★★ ⚠ same type
MAP3K3 c.126+67G>T Benign ★★ same type
MAP3K3 c.1475-146T>C Benign ★★ same type
MAP3K3 c.168-35A>G Benign ★★ same type
MAP3K3 c.268-98T>C Benign ★★ same type
MAP3K3 c.382-260A>G Benign ★★ 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/map3k3-p-val281met (accessed [today's date]).

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