Is MAP2K2 p.Ala80= (c.240G>A) pathogenic?

MAP2K2 p.Ala80= (c.240G>A) is classified Likely benign in MAP2K2 (ClinVar, Expert panel, 7 submitters; last evaluated 2017-05-09). Ultra-rare (popmax 0.0648%, sas); Associated with RASopathy.

What condition is associated with MAP2K2 p.Ala80= (c.240G>A)?

MAP2K2 p.Ala80= (c.240G>A) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Ala80= (c.240G>A) in the general population?

MAP2K2 p.Ala80= (c.240G>A) is ultra-rare (popmax 0.0648%, sas) (gnomAD).

MAP2K2 p.Ala80=

c.240G>A · rs543217722 · VCV378913

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0648%, sas)

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.240G>A (p.Ala80=) variant in the MAP2K2 gene is 0.0284% (9/16506) of South 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -9.9	GERP -3.9
Overall
CADD	5.459	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0648% South Asian · 59/91,084 alleles

Filtering AF 0.0515% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0467%

Overall 0.00595% 96/1,614,148 alleles · ultra-rare exomes 88/1,461,806 · genomes 8/152,342 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0648%	1,544
Admixed American	0.0117%	8,576
African / African-American	0.00933%	10,722
East Asian	0.00223%	44,888
European (non-Finnish)	0.00178%	56,192
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Ala80=
Coding: c.240G>A
MANE Select: NM_030662
dbSNP: rs543217722
Type: single nucleotide variant
Location: chr19:4117482 (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.Ala80Thr 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-ala80 (accessed [today's date]).

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