Is MAP2K2 p.Arg303His (c.908G>A) pathogenic?

MAP2K2 p.Arg303His (c.908G>A) is classified Uncertain significance in MAP2K2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-26). AlphaMissense: likely benign (0.1967); Very rare (popmax 0.00133%, afr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Arg303His (c.908G>A)?

MAP2K2 p.Arg303His (c.908G>A) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Arg303His (c.908G>A) in the general population?

MAP2K2 p.Arg303His (c.908G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about MAP2K2 p.Arg303His (c.908G>A)?

AlphaMissense predicts likely benign (score 0.1967) — an in-silico prediction, not a clinical call.

MAP2K2 p.Arg303His

c.908G>A · rs1251433138 · VCV1381883

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1967 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.1967	likely benign
REVEL	0.698	pathogenic-leaning
SaProt	LLR -7.99	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 0.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	27.6	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 0.00133% African / African-American · 1/74,924 alleles

Filtering AF 0.000617% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000475%

Overall 0.000936% 15/1,602,606 alleles · very rare exomes 15/1,450,276 · genomes 0/152,330 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,924
South Asian	0.00111%	89,766
European (non-Finnish)	0.00111%	90,424

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.Arg303His
Coding: c.908G>A
MANE Select: NM_030662
dbSNP: rs1251433138
Type: single nucleotide variant
Location: chr19:4099212 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 303: the protein kinase domain; the 'disordered' region

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.Arg303Cys Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Arg303= Likely benign ★★ same residue
MAP2K2 p.Arg303fs Uncertain significance ★ same residue
MAP2K2 p.Arg303Leu 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

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-arg303his (accessed [today's date]).

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