Is MAP3K2 p.Ile154Met (c.462A>G) pathogenic?

MAP3K2 p.Ile154Met (c.462A>G) is classified Uncertain significance in MAP3K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-09). AlphaMissense: likely benign (0.0641); Very rare (popmax 0.00449%, eas).

How common is MAP3K2 p.Ile154Met (c.462A>G) in the general population?

MAP3K2 p.Ile154Met (c.462A>G) is very rare (popmax 0.00449%, eas) (gnomAD).

What do computational predictors say about MAP3K2 p.Ile154Met (c.462A>G)?

AlphaMissense predicts likely benign (score 0.0641) — an in-silico prediction, not a clinical call.

MAP3K2 p.Ile154Met

c.462A>G · VCV3870204

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0641 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00449%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0641	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -6.95	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 -0.082	GERP -5.5, phastCons 0.84
Regional constraint	o/e 0.89	unconstrained · MANE · 25 kb · p 0.016 · regional, not allelic
Overall
CADD	15.04	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 0.00449% East Asian · 2/44,572 alleles

Filtering AF 0.000744% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000278%

Overall 0.0007% 11/1,571,440 alleles · very rare exomes 7/1,419,212 · genomes 4/152,228 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00449%	22,286
Admixed American	0.00168%	59,616
South Asian	0.00111%	90,090
European (non-Finnish)	0.000613%	163,227

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.Ile154Met
Coding: c.462A>G
MANE Select: NM_001371910
Type: single nucleotide variant
Location: chr2:127329925 (GRCh38)
Gene constraint: LOEUF 0.6 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 68.27 · 9 PDB
Residue 154: the 'disordered' region

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-ile154met (accessed [today's date]).

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