Is MAPK4 p.Ile8Val (c.22A>G) pathogenic?

MAPK4 p.Ile8Val (c.22A>G) is classified Uncertain significance in MAPK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). AlphaMissense: likely benign (0.0711); Very rare (popmax 0.00432%, nfe).

How common is MAPK4 p.Ile8Val (c.22A>G) in the general population?

MAPK4 p.Ile8Val (c.22A>G) is very rare (popmax 0.00432%, nfe) (gnomAD).

What do computational predictors say about MAPK4 p.Ile8Val (c.22A>G)?

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

MAPK4 p.Ile8Val

c.22A>G · rs772545058 · VCV3123274

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

very rare (popmax 0.00432%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0711	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -5.28	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 0.007	GERP -3.7, phastCons 0.072
Regional constraint	o/e 0.83	unconstrained · MANE · 62 kb · p 0.00058 · regional, not allelic
Overall
CADD	4.428	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 0.00432% European (non-Finnish) · 51/1,179,342 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00329% 53/1,612,704 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00432%	23,124
Admixed American	0.00334%	29,980

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.Ile8Val
Coding: c.22A>G
MANE Select: NM_002747
dbSNP: rs772545058
Type: single nucleotide variant
Location: chr18:50663980 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.04

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

Similar variants

MAPK4 p.Ile8Thr Uncertain significance ★ ⚠ same residue
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

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-ile8val (accessed [today's date]).

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