Is MAP2K2 p.Val377Ala (c.1130T>C) pathogenic?

MAP2K2 p.Val377Ala (c.1130T>C) is classified Uncertain significance in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-22). AlphaMissense: ambiguous (0.3406); Very rare (popmax 0.00118%, sas); Associated with RASopathy.

What condition is associated with MAP2K2 p.Val377Ala (c.1130T>C)?

MAP2K2 p.Val377Ala (c.1130T>C) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Val377Ala (c.1130T>C) in the general population?

MAP2K2 p.Val377Ala (c.1130T>C) is very rare (popmax 0.00118%, sas) (gnomAD).

What do computational predictors say about MAP2K2 p.Val377Ala (c.1130T>C)?

AlphaMissense predicts ambiguous (score 0.3406) — an in-silico prediction, not a clinical call.

MAP2K2 p.Val377Ala

c.1130T>C · rs2040846741 · VCV2697388

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3406 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00118%, sas)

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.3406	ambiguous
REVEL	0.478	indeterminate
SaProt	LLR -11.48	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.94, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	24.6	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 0.00118% South Asian · 1/84,782 alleles

Overall 0.000128% 2/1,559,854 alleles · very rare exomes 2/1,407,620 · genomes 0/152,234 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00118%	84,782
European (non-Finnish)	8.68e-05%	1,151,714

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.Val377Ala
Coding: c.1130T>C
MANE Select: NM_030662
dbSNP: rs2040846741
Type: single nucleotide variant
Location: chr19:4090671 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB

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.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
MAP2K2 p.Arg231Leu Uncertain significance ★★★ ⚠ same condition
MAP2K2 p.Arg281Gln 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-val377ala (accessed [today's date]).

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