Is MAP2K2 p.Arg297Trp (c.889C>T) pathogenic?

MAP2K2 p.Arg297Trp (c.889C>T) is classified Conflicting classifications of pathogenicity in MAP2K2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-27). AlphaMissense: likely benign (0.1631); Ultra-rare (popmax 0.0347%, afr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Arg297Trp (c.889C>T)?

MAP2K2 p.Arg297Trp (c.889C>T) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Arg297Trp (c.889C>T) in the general population?

MAP2K2 p.Arg297Trp (c.889C>T) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

What do computational predictors say about MAP2K2 p.Arg297Trp (c.889C>T)?

AlphaMissense predicts likely benign (score 0.1631) — an in-silico prediction, not a clinical call.

MAP2K2 p.Arg297Trp

c.889C>T · rs562352756 · VCV40831

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1631 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.1631	likely benign
REVEL	0.283	benign-leaning
SaProt	LLR -11.88	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.8	GERP -2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	23.2	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 0.0347% African / African-American · 26/74,958 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00262% 42/1,604,586 alleles · ultra-rare exomes 21/1,452,240 · genomes 21/152,346 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0347%	2,883
Admixed American	0.0034%	29,372
Remaining individualsnot grpmax-eligible	0.00161%	62,072
South Asian	0.00111%	89,948
European (non-Finnish)	0.00102%	98,017

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.Arg297Trp
Coding: c.889C>T
MANE Select: NM_030662
dbSNP: rs562352756
Type: single nucleotide variant
Location: chr19:4099231 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 297: 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.Arg297Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
MAP2K2 p.Arg297= Likely benign ★ 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
MAP2K2 p.Arg231His Uncertain significance ★★★ ⚠ 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-arg297trp (accessed [today's date]).

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