Is MAP2K3 p.Ala303Val (c.908C>T) pathogenic?

MAP2K3 p.Ala303Val (c.908C>T) is classified Uncertain significance in MAP2K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-01). AlphaMissense: likely benign (0.1218); Ultra-rare (popmax 0.0186%, eas).

How common is MAP2K3 p.Ala303Val (c.908C>T) in the general population?

MAP2K3 p.Ala303Val (c.908C>T) is ultra-rare (popmax 0.0186%, eas) (gnomAD).

What do computational predictors say about MAP2K3 p.Ala303Val (c.908C>T)?

AlphaMissense predicts likely benign (score 0.1218) — an in-silico prediction, not a clinical call.

MAP2K3 p.Ala303Val

c.908C>T · rs768951364 · VCV2348677

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1218 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0186%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1218	likely benign
REVEL	0.276	benign-leaning
SaProt	LLR -9.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.59 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.3	GERP 1.5, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 2,006 bp · p 0.04 · regional, not allelic
Overall
CADD	24.6	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 0.0186% East Asian · 8/42,920 alleles

Filtering AF 0.00918% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00676%

Overall 0.0005% 8/1,600,146 alleles · ultra-rare exomes 7/1,447,922 · genomes 1/152,224 · joint denominator

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: MAP2K3
Protein: p.Ala303Val
Coding: c.908C>T
MANE Select: NM_145109
dbSNP: rs768951364
Type: single nucleotide variant
Location: chr17:21312275 (GRCh38)
Gene constraint: LOEUF 0.993 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.13
Residue 303: the protein kinase domain

Full MAP2K3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP2K3 p.Leu215Trp Uncertain significance ★★ ⚠ same type
MAP2K3 c.568+10C>T Benign ★★ same type
MAP2K3 p.Ala220= Benign ★★ same type
MAP2K3 p.Ala225= Likely benign ★★ same type
MAP2K3 p.Leu25= Benign ★★ same type
MAP2K3 p.Leu319= Likely benign ★★ same type
MAP2K3 p.Pro40Thr Benign ★★ same type
MAP2K3 p.Ser286= Likely 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/map2k3-p-ala303val (accessed [today's date]).

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