Is MAP2K2 p.Ala380= (c.1140C>T) pathogenic?

MAP2K2 p.Ala380= (c.1140C>T) is classified Likely benign in MAP2K2 (ClinVar, Expert panel, 10 submitters; last evaluated 2017-05-09). Ultra-rare (popmax 0.0666%, afr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Ala380= (c.1140C>T)?

MAP2K2 p.Ala380= (c.1140C>T) is associated with RASopathy, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is MAP2K2 p.Ala380= (c.1140C>T) in the general population?

MAP2K2 p.Ala380= (c.1140C>T) is ultra-rare (popmax 0.0666%, afr) (gnomAD).

MAP2K2 p.Ala380=

c.1140C>T · rs146618055 · VCV50938

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0666%, afr)

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Likely Benign for RASopathy. Applied ACMG criteria (verbatim):

BS1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.1140C>T (p.Ala380=) variant in the MAP2K2 gene is 0.003% (2/796) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8	GERP -3.9
Overall
CADD	0.515	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0666% African / African-American · 49/73,606 alleles

Filtering AF 0.0516% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0464%

Overall 0.0274% 428/1,559,242 alleles · ultra-rare exomes 371/1,406,918 · genomes 57/152,324 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0666%	1,502
East Asian	0.0407%	2,454
Middle Eastern	0.0334%	2,993
European (non-Finnish)	0.029%	3,448
Remaining individualsnot grpmax-eligible	0.0281%	3,556
Admixed American	0.0116%	8,656
South Asian	0.00354%	28,235

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.Ala380=
Coding: c.1140C>T
MANE Select: NM_030662
dbSNP: rs146618055
Type: single nucleotide variant
Location: chr19:4090661 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 380: 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

Also linked: Noonan syndrome and Noonan-related syndrome

Similar variants

MAP2K2 p.Ala380Val Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Ala380Thr 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-ala380 (accessed [today's date]).

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