Is MAP2K2 p.Arg371Gln (c.1112G>A) pathogenic?

MAP2K2 p.Arg371Gln (c.1112G>A) is classified Uncertain significance in MAP2K2 (ClinVar, Expert panel, 7 submitters; last evaluated 2019-08-26). AlphaMissense: likely benign (0.0817); Very rare (popmax 0.00773%, amr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Arg371Gln (c.1112G>A)?

MAP2K2 p.Arg371Gln (c.1112G>A) is associated with RASopathy, cardiofaciocutaneous syndrome 4 (ClinVar).

How common is MAP2K2 p.Arg371Gln (c.1112G>A) in the general population?

MAP2K2 p.Arg371Gln (c.1112G>A) is very rare (popmax 0.00773%, amr) (gnomAD).

What do computational predictors say about MAP2K2 p.Arg371Gln (c.1112G>A)?

AlphaMissense predicts likely benign (score 0.0817) — an in-silico prediction, not a clinical call.

MAP2K2 p.Arg371Gln

c.1112G>A · rs730880514 · VCV40842

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0817 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00773%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Uncertain Significance for RASopathy. Applied ACMG criteria (verbatim):

PP2 BP5

Curation rationale (ClinGen, verbatim)

The p.Arg371Gln variant in MAP2K2 has been identified in 0.00401% (lower bound of the 95% CI of 7/81796) of non-Finnish European chromosomes in gnomAD (https://gnomad.broadinstitute.org) (BS1 not met). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants, and pathogenic missense variants are common (PP2; PMID: 29493581). This variant has been observed in many individuals with varying clnical presentations that lack clear associations with a RASopathy. This variant was identified in 1 individual with syncope and atrial fibrillation, who carried an additional pathogenic variant in a cardiomyopathy gene sufficient to explain their clinical presentation (BP5; Invitae internal data). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP2, BP5.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0817	likely benign
REVEL	0.341	indeterminate
SaProt	LLR -8.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; 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	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00773% Admixed American · 4/51,764 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00391% 61/1,558,380 alleles · very rare exomes 53/1,406,206 · genomes 8/152,174 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00828%	12,082
Admixed Americangrpmax	0.00773%	12,941
European (non-Finnish)	0.00426%	23,489
African / African-American	0.00272%	36,736
South Asian	0.00118%	84,672

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.Arg371Gln
Coding: c.1112G>A
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

Also linked: cardiofaciocutaneous syndrome 4

Similar variants

MAP2K2 p.Arg371Trp Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Arg371Leu 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
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-arg371gln (accessed [today's date]).

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