Is MAP2K2 p.Arg371Leu (c.1112G>T) pathogenic?

MAP2K2 p.Arg371Leu (c.1112G>T) is classified Uncertain significance in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-09). AlphaMissense: likely benign (0.1631); Very rare (popmax 0.00193%, amr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Arg371Leu (c.1112G>T)?

MAP2K2 p.Arg371Leu (c.1112G>T) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Arg371Leu (c.1112G>T) in the general population?

MAP2K2 p.Arg371Leu (c.1112G>T) is very rare (popmax 0.00193%, amr) (gnomAD).

What do computational predictors say about MAP2K2 p.Arg371Leu (c.1112G>T)?

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

MAP2K2 p.Arg371Leu

c.1112G>T · rs730880514 · VCV2199936

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1631 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00193%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.1631	likely benign
REVEL	0.494	indeterminate
SaProt	LLR -10.60	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 5.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	24.5	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 0.00193% Admixed American · 1/51,764 alleles

Filtering AF 0.000299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000216%

Overall 0.000706% 11/1,558,380 alleles · very rare exomes 9/1,406,206 · genomes 2/152,174 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00193%	51,764
Remaining individualsnot grpmax-eligible	0.00166%	60,412
African / African-American	0.00136%	73,472
European (non-Finnish)	0.000695%	143,871

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.Arg371Leu
Coding: c.1112G>T
MANE Select: NM_030662
dbSNP: rs730880514
Type: single nucleotide variant
Location: chr19:4090689 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 371: 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.Arg371Gln Uncertain significance ★★★ ⚠ same residue
MAP2K2 p.Arg371Trp 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
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-arg371leu (accessed [today's date]).

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