Is MAP2K2 p.Asp271Glu (c.813C>G) pathogenic?

MAP2K2 p.Asp271Glu (c.813C>G) is classified Conflicting classifications of pathogenicity in MAP2K2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.1657); Ultra-rare (popmax 0.0203%, amr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Asp271Glu (c.813C>G)?

MAP2K2 p.Asp271Glu (c.813C>G) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Asp271Glu (c.813C>G) in the general population?

MAP2K2 p.Asp271Glu (c.813C>G) is ultra-rare (popmax 0.0203%, amr) (gnomAD).

What do computational predictors say about MAP2K2 p.Asp271Glu (c.813C>G)?

AlphaMissense predicts likely benign (score 0.1657) — an in-silico prediction, not a clinical call.

MAP2K2 p.Asp271Glu

c.813C>G · rs201726622 · VCV1092325

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1657 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0203%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.1657	likely benign
REVEL	0.282	benign-leaning
SaProt	LLR -7.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -3.9
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	7.873	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 0.0203% Admixed American · 12/59,090 alleles

Filtering AF 0.0117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00911%

Overall 0.00604% 97/1,606,922 alleles · ultra-rare exomes 89/1,454,706 · genomes 8/152,216 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0203%	4,924
Middle Eastern	0.0164%	6,080
European (non-Finnish)	0.0068%	14,715
Remaining individualsnot grpmax-eligible	0.00482%	20,727
African / African-American	0.00134%	74,834

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.Asp271Glu
Coding: c.813C>G
MANE Select: NM_030662
dbSNP: rs201726622
Type: single nucleotide variant
Location: chr19:4099307 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 271: the protein kinase domain; 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

Similar variants

MAP2K2 p.Asp271= Likely benign ★★★ same residue
MAP2K2 p.Asp271Asn Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Asp271Tyr 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-asp271glu (accessed [today's date]).

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