Is MAPK4 p.Asp111Asn (c.331G>A) pathogenic?

MAPK4 p.Asp111Asn (c.331G>A) is classified Uncertain significance in MAPK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-11). AlphaMissense: likely pathogenic (0.8028); Ultra-rare (popmax 0.0773%, afr).

How common is MAPK4 p.Asp111Asn (c.331G>A) in the general population?

MAPK4 p.Asp111Asn (c.331G>A) is ultra-rare (popmax 0.0773%, afr) (gnomAD).

What do computational predictors say about MAPK4 p.Asp111Asn (c.331G>A)?

AlphaMissense predicts likely pathogenic (score 0.8028) — an in-silico prediction, not a clinical call.

MAPK4 p.Asp111Asn

c.331G>A · rs200812352 · VCV2459081

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8028 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0773%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8028	likely pathogenic
REVEL	0.415	indeterminate
SaProt	LLR -8.35	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 62 kb · p 0.00058 · regional, not allelic
Overall
CADD	28.6	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 0.0773% African / African-American · 58/75,042 alleles

Filtering AF 0.0613% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0556%

Overall 0.00452% 73/1,613,440 alleles · ultra-rare exomes 42/1,461,152 · genomes 31/152,288 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0773%	1,294
East Asian	0.00446%	22,429
Admixed American	0.00333%	30,009
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)	0.000848%	117,968

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.Asp111Asn
Coding: c.331G>A
MANE Select: NM_002747
dbSNP: rs200812352
Type: single nucleotide variant
Location: chr18:50664289 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.04
Residue 111: the protein kinase domain

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-asp111asn (accessed [today's date]).

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