Is MAP3K2 p.Tyr371Cys (c.1112A>G) pathogenic?

MAP3K2 p.Tyr371Cys (c.1112A>G) is classified Uncertain significance in MAP3K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: ambiguous (0.3833); Ultra-rare (popmax 0.0155%, nfe).

How common is MAP3K2 p.Tyr371Cys (c.1112A>G) in the general population?

MAP3K2 p.Tyr371Cys (c.1112A>G) is ultra-rare (popmax 0.0155%, nfe) (gnomAD).

What do computational predictors say about MAP3K2 p.Tyr371Cys (c.1112A>G)?

AlphaMissense predicts ambiguous (score 0.3833) — an in-silico prediction, not a clinical call.

MAP3K2 p.Tyr371Cys

c.1112A>G · rs750916978 · VCV2353688

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3833 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0155%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3833	ambiguous
REVEL	0.478	indeterminate
SaProt	LLR -11.09	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 25 kb · p 0.016 · regional, not allelic
Overall
CADD	27.7	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 0.0155% European (non-Finnish) · 183/1,178,972 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.013%

Overall 0.0127% 205/1,611,440 alleles · ultra-rare exomes 196/1,459,246 · genomes 9/152,194 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.016%	6,235
European (non-Finnish)grpmax	0.0155%	6,442
Admixed American	0.0118%	8,496
South Asian	0.00552%	18,112

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: MAP3K2
Protein: p.Tyr371Cys
Coding: c.1112A>G
MANE Select: NM_001371910
dbSNP: rs750916978
Type: single nucleotide variant
Location: chr2:127318251 (GRCh38)
Gene constraint: LOEUF 0.6 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 68.27 · 9 PDB
Residue 371: a binding site; the protein kinase domain

Full MAP3K2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K2 p.Thr293= Benign ★★ same type
MAP3K2 p.Tyr422= Benign ★★ same type
MAP3K2 p.Ala178Val Uncertain significance ★ ⚠ same type
MAP3K2 p.Ala487Thr Uncertain significance ★ ⚠ same type
MAP3K2 p.Ala607Thr Uncertain significance ★ ⚠ same type
MAP3K2 p.Arg151Trp Uncertain significance ★ ⚠ same type
MAP3K2 p.Arg286Ile Uncertain significance ★ ⚠ same type
MAP3K2 p.Arg328Lys 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/map3k2-p-tyr371cys (accessed [today's date]).

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