Is MAP3K2 p.Arg151Trp (c.451C>T) pathogenic?

MAP3K2 p.Arg151Trp (c.451C>T) is classified Uncertain significance in MAP3K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: likely benign (0.1213); Very rare (popmax 0.00448%, eas).

How common is MAP3K2 p.Arg151Trp (c.451C>T) in the general population?

MAP3K2 p.Arg151Trp (c.451C>T) is very rare (popmax 0.00448%, eas) (gnomAD).

What do computational predictors say about MAP3K2 p.Arg151Trp (c.451C>T)?

AlphaMissense predicts likely benign (score 0.1213) — an in-silico prediction, not a clinical call.

MAP3K2 p.Arg151Trp

c.451C>T · VCV4103322

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1213 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00448%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1213	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -8.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 25 kb · p 0.016 · regional, not allelic
Overall
CADD	24.0	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 0.00448% East Asian · 2/44,682 alleles

Filtering AF 0.00123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00105%

Overall 0.00163% 26/1,599,602 alleles · very rare exomes 24/1,447,482 · genomes 2/152,120 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00448%	22,341
Remaining individualsnot grpmax-eligible	0.00323%	30,965
European (non-Finnish)	0.00188%	53,098

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.Arg151Trp
Coding: c.451C>T
MANE Select: NM_001371910
Type: single nucleotide variant
Location: chr2:127329936 (GRCh38)
Gene constraint: LOEUF 0.6 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 68.27 · 9 PDB

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.Arg286Ile Uncertain significance ★ ⚠ same type
MAP3K2 p.Arg328Lys Uncertain significance ★ ⚠ same type
MAP3K2 p.Arg465His 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-arg151trp (accessed [today's date]).

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