Is MAP2K2 p.Ala176Val (c.527C>T) pathogenic?

MAP2K2 p.Ala176Val (c.527C>T) is classified Conflicting classifications of pathogenicity in MAP2K2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.7893); Very rare (popmax 0.00452%, sas); Associated with RASopathy.

What condition is associated with MAP2K2 p.Ala176Val (c.527C>T)?

MAP2K2 p.Ala176Val (c.527C>T) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Ala176Val (c.527C>T) in the general population?

MAP2K2 p.Ala176Val (c.527C>T) is very rare (popmax 0.00452%, sas) (gnomAD).

What do computational predictors say about MAP2K2 p.Ala176Val (c.527C>T)?

AlphaMissense predicts likely pathogenic (score 0.7893) — an in-silico prediction, not a clinical call.

MAP2K2 p.Ala176Val

c.527C>T · rs775661458 · VCV1363165

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00452%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.7893	likely pathogenic
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -14.44	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	33.0	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 0.00452% South Asian · 4/88,546 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000911%

Overall 0.00125% 20/1,598,252 alleles · very rare exomes 19/1,445,938 · genomes 1/152,314 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00452%	22,136
East Asian	0.00225%	44,392
Admixed American	0.00174%	57,626
European (non-Finnish)	0.00119%	83,843

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: MAP2K2
Protein: p.Ala176Val
Coding: c.527C>T
MANE Select: NM_030662
dbSNP: rs775661458
Type: single nucleotide variant
Location: chr19:4102377 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 176: the protein kinase domain; an α-helix

Full MAP2K2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

RASopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAP2K2 p.Ala176= Uncertain significance ★★ same residue
MAP2K2 p.Ala176Thr Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Glu207Lys Likely pathogenic ★★★ same condition
MAP2K2 p.Phe57Cys Pathogenic ★★★ same condition
MAP2K2 p.Pro128Gln Pathogenic ★★★ same condition
MAP2K2 p.Tyr134Cys Likely pathogenic ★★★ same condition
MAP2K2 p.Tyr134His Pathogenic ★★★ same condition
MAP2K2 p.Arg231His Uncertain significance ★★★ ⚠ same condition

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/map2k2-p-ala176val (accessed [today's date]).

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