Is MAP2K2 p.Ala80Val (c.239C>T) pathogenic?

MAP2K2 p.Ala80Val (c.239C>T) is classified Uncertain significance in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-12). AlphaMissense: likely pathogenic (0.5735); Very rare (popmax 0.004%, afr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Ala80Val (c.239C>T)?

MAP2K2 p.Ala80Val (c.239C>T) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Ala80Val (c.239C>T) in the general population?

MAP2K2 p.Ala80Val (c.239C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about MAP2K2 p.Ala80Val (c.239C>T)?

AlphaMissense predicts likely pathogenic (score 0.5735) — an in-silico prediction, not a clinical call.

MAP2K2 p.Ala80Val

c.239C>T · rs142271248 · VCV958648

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5735 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.5735	likely pathogenic
REVEL	0.621	indeterminate
SaProt	LLR -9.61	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP -0.68, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	32.0	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 0.004% African / African-American · 3/74,930 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,948 alleles · very rare exomes 0/1,461,778 · genomes 3/152,170 · joint denominator

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.Ala80Val
Coding: c.239C>T
MANE Select: NM_030662
dbSNP: rs142271248
Type: single nucleotide variant
Location: chr19:4117483 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 80: the protein kinase domain; a β-strand; a binding site

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.Ala80= Likely benign ★★★ same residue
MAP2K2 p.Ala80Thr Likely benign ★★ same residue
MAP2K2 p.Ala80Ser 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

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-ala80val (accessed [today's date]).

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