Is MAP2K2 p.Arg303Cys (c.907C>T) pathogenic?

MAP2K2 p.Arg303Cys (c.907C>T) is classified Uncertain significance in MAP2K2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-11). AlphaMissense: likely benign (0.2727); Ultra-rare (popmax 0.0169%, mid); Associated with RASopathy.

What condition is associated with MAP2K2 p.Arg303Cys (c.907C>T)?

MAP2K2 p.Arg303Cys (c.907C>T) is associated with RASopathy, cardiofaciocutaneous syndrome 4, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is MAP2K2 p.Arg303Cys (c.907C>T) in the general population?

MAP2K2 p.Arg303Cys (c.907C>T) is ultra-rare (popmax 0.0169%, mid) (gnomAD).

What do computational predictors say about MAP2K2 p.Arg303Cys (c.907C>T)?

AlphaMissense predicts likely benign (score 0.2727) — an in-silico prediction, not a clinical call.

MAP2K2 p.Arg303Cys

c.907C>T · rs770521279 · VCV1334259

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2727 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.2727	likely benign
REVEL	0.754	pathogenic-leaning
SaProt	LLR -11.44	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.6	GERP -0.52, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · 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 0.0169% Middle Eastern · 1/5,922 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00105%

Overall 0.00168% 27/1,602,718 alleles · ultra-rare exomes 25/1,450,404 · genomes 2/152,314 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0169%	5,922
South Asian	0.00334%	29,935
East Asian	0.00225%	44,470
European (non-Finnish)	0.00187%	53,435

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.Arg303Cys
Coding: c.907C>T
MANE Select: NM_030662
dbSNP: rs770521279
Type: single nucleotide variant
Location: chr19:4099213 (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

Also linked: cardiofaciocutaneous syndrome 4 Noonan syndrome and Noonan-related syndrome

Similar variants

MAP2K2 p.Arg303His 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.Phe57Val Pathogenic ★★★ same condition
MAP2K2 p.Pro128Gln 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-arg303cys (accessed [today's date]).

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