Is MAP2K2 p.Arg112Trp (c.334C>T) pathogenic?

MAP2K2 p.Arg112Trp (c.334C>T) is classified Likely pathogenic in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely pathogenic (0.9263); Very rare (popmax 0.00167%, amr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Arg112Trp (c.334C>T)?

MAP2K2 p.Arg112Trp (c.334C>T) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Arg112Trp (c.334C>T) in the general population?

MAP2K2 p.Arg112Trp (c.334C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about MAP2K2 p.Arg112Trp (c.334C>T)?

AlphaMissense predicts likely pathogenic (score 0.9263) — an in-silico prediction, not a clinical call.

MAP2K2 p.Arg112Trp

c.334C>T · rs201129499 · VCV1963465

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9263 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.9263	likely pathogenic ✓ concordant with ClinVar
REVEL	0.779	moderately pathogenic-leaning
SaProt	LLR -15.20	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	33.0	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 0.00167% Admixed American · 1/60,008 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000744% 12/1,613,540 alleles · very rare exomes 11/1,461,316 · genomes 1/152,224 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,240
Admixed Americangrpmax	0.00167%	60,008
Finnishnot grpmax-eligible	0.00157%	63,524
South Asian	0.0011%	91,094
European (non-Finnish)	0.000593%	168,572

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg112Trp
Coding: c.334C>T
MANE Select: NM_030662
dbSNP: rs201129499
Type: single nucleotide variant
Location: chr19:4110625 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 112: 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.Arg112Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
MAP2K2 p.Arg112Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MAP2K2 p.Arg112= 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-arg112trp (accessed [today's date]).

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