Is MAP2K2 p.Ala80Thr (c.238G>A) pathogenic?

MAP2K2 p.Ala80Thr (c.238G>A) is classified Likely benign in MAP2K2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-10). AlphaMissense: ambiguous (0.4192); Ultra-rare (popmax 0.0156%, eas); Associated with RASopathy.

What condition is associated with MAP2K2 p.Ala80Thr (c.238G>A)?

MAP2K2 p.Ala80Thr (c.238G>A) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Ala80Thr (c.238G>A) in the general population?

MAP2K2 p.Ala80Thr (c.238G>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about MAP2K2 p.Ala80Thr (c.238G>A)?

AlphaMissense predicts ambiguous (score 0.4192) — an in-silico prediction, not a clinical call.

MAP2K2 p.Ala80Thr

c.238G>A · rs751795549 · VCV1496025

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4192 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.4192	ambiguous
REVEL	0.568	indeterminate
SaProt	LLR -9.42	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -0.68, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	31.0	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 0.0156% East Asian · 7/44,896 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.0013% 21/1,614,060 alleles · ultra-rare exomes 20/1,461,826 · genomes 1/152,234 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,414
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.00133%	74,936
South Asian	0.0011%	91,092
European (non-Finnish)	0.000763%	131,117

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.Ala80Thr
Coding: c.238G>A
MANE Select: NM_030662
dbSNP: rs751795549
Type: single nucleotide variant
Location: chr19:4117484 (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.Ala80Ser Uncertain significance ★ ⚠ same residue
MAP2K2 p.Ala80Val 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-ala80thr (accessed [today's date]).

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