Is MAP2K2 p.Arg281Trp (c.841C>T) pathogenic?

MAP2K2 p.Arg281Trp (c.841C>T) is classified Conflicting classifications of pathogenicity in MAP2K2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-02-26). AlphaMissense: likely benign (0.09); Very rare (popmax 0.00535%, afr); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K2 p.Arg281Trp (c.841C>T)?

MAP2K2 p.Arg281Trp (c.841C>T) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is MAP2K2 p.Arg281Trp (c.841C>T) in the general population?

MAP2K2 p.Arg281Trp (c.841C>T) is very rare (popmax 0.00535%, afr) (gnomAD).

What do computational predictors say about MAP2K2 p.Arg281Trp (c.841C>T)?

AlphaMissense predicts likely benign (score 0.09) — an in-silico prediction, not a clinical call.

MAP2K2 p.Arg281Trp

c.841C>T · rs759998177 · VCV917722

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.09 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00535%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.09	likely benign
REVEL	0.357	indeterminate
SaProt	LLR -12.39	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -3.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	23.8	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 0.00535% African / African-American · 4/74,818 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00193% 31/1,605,404 alleles · very rare exomes 26/1,453,226 · genomes 5/152,178 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00535%	18,704
Admixed American	0.0051%	19,627
Remaining individualsnot grpmax-eligible	0.00483%	20,707
South Asian	0.00334%	29,975
East Asian	0.00225%	44,518
European (non-Finnish)	0.00144%	69,209

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.Arg281Trp
Coding: c.841C>T
MANE Select: NM_030662
dbSNP: rs759998177
Type: single nucleotide variant
Location: chr19:4099279 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 281: the protein kinase domain

Full MAP2K2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: RASopathy

Similar variants

MAP2K2 p.Arg281Gln Uncertain significance ★★★ ⚠ same residue
MAP2K2 p.Arg281Pro Uncertain significance ★ ⚠ same residue
MAP2K2 p.Arg281= 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

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-arg281trp (accessed [today's date]).

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