Is MAPK4 p.Arg371Gln (c.1112G>A) pathogenic?

MAPK4 p.Arg371Gln (c.1112G>A) is classified Uncertain significance in MAPK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely benign (0.0711); Ultra-rare (popmax 0.0286%, amr).

How common is MAPK4 p.Arg371Gln (c.1112G>A) in the general population?

MAPK4 p.Arg371Gln (c.1112G>A) is ultra-rare (popmax 0.0286%, amr) (gnomAD).

What do computational predictors say about MAPK4 p.Arg371Gln (c.1112G>A)?

AlphaMissense predicts likely benign (score 0.0711) — an in-silico prediction, not a clinical call.

MAPK4 p.Arg371Gln

c.1112G>A · rs3752089 · VCV3123272

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0711 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0286%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0711	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -6.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 3,740 bp · p 0.94 · regional, not allelic
Overall
CADD	21.5	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 0.0286% Admixed American · 17/59,516 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0149%

Overall 0.0015% 24/1,595,608 alleles · ultra-rare exomes 19/1,443,270 · genomes 5/152,338 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0286%	3,501
East Asian	0.00451%	22,159
South Asian	0.00111%	90,382
European (non-Finnish)	0.000343%	291,459

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: MAPK4
Protein: p.Arg371Gln
Coding: c.1112G>A
MANE Select: NM_002747
dbSNP: rs3752089
Type: single nucleotide variant
Location: chr18:50729202 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.04
Residue 371: a UniProt-annotated variant site (in)

Full MAPK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPK4 p.Ala2Ser Uncertain significance ★ ⚠ same type
MAPK4 p.Ala473Val Uncertain significance ★ ⚠ same type
MAPK4 p.Ala481Gly Uncertain significance ★ ⚠ same type
MAPK4 p.Ala487Asp Uncertain significance ★ ⚠ same type
MAPK4 p.Ala9Ser Uncertain significance ★ ⚠ same type
MAPK4 p.Arg195Cys Uncertain significance ★ ⚠ same type
MAPK4 p.Arg198Leu Uncertain significance ★ ⚠ same type
MAPK4 p.Arg19His Uncertain significance ★ ⚠ same type

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/mapk4-p-arg371gln (accessed [today's date]).

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