Is MAPK8IP3 p.Val421Ala (c.1262T>C) pathogenic?

MAPK8IP3 p.Val421Ala (c.1262T>C) is classified Uncertain significance in MAPK8IP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-30). AlphaMissense: likely pathogenic (0.9356); Very rare (popmax 8.47e-05%, nfe); Associated with intellectual disability.

What condition is associated with MAPK8IP3 p.Val421Ala (c.1262T>C)?

MAPK8IP3 p.Val421Ala (c.1262T>C) is associated with intellectual disability (ClinVar).

How common is MAPK8IP3 p.Val421Ala (c.1262T>C) in the general population?

MAPK8IP3 p.Val421Ala (c.1262T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about MAPK8IP3 p.Val421Ala (c.1262T>C)?

AlphaMissense predicts likely pathogenic (score 0.9356) — an in-silico prediction, not a clinical call.

MAPK8IP3 p.Val421Ala

c.1262T>C · VCV4075192

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9356 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.9356	likely pathogenic
REVEL	0.272	benign-leaning
SaProt	LLR -12.58	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 35 kb · p 6.4e-05 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V420A vs ClinVar V421A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,000 alleles

Overall 6.84e-05% 1/1,461,842 alleles · very rare

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: MAPK8IP3
Protein: p.Val421Ala
Coding: c.1262T>C
MANE Select: NM_001318852
Type: single nucleotide variant
Location: chr16:1759973 (GRCh38)
Gene constraint: LOEUF 0.407 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.19 · 5 PDB
Residue 420 UniProt numbering: a UniProt-annotated variant site (in nedba)

Full MAPK8IP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAPK8IP3 p.Val421Met Uncertain significance ★ ⚠ same residue
MAPK8IP3 p.Arg149Gln Uncertain significance ★ ⚠ same condition
MAPK8IP3 p.Arg1147Cys Pathogenic/Likely pathogenic ★★ same type
MAPK8IP3 p.Arg579Cys Pathogenic/Likely pathogenic ★★ same type
MAPK8IP3 p.Gln468Ter Pathogenic/Likely pathogenic ★★ same type
MAPK8IP3 p.Glu27Ter Likely pathogenic ★★ same type
MAPK8IP3 p.Glu462Gly Likely pathogenic ★★ same type
MAPK8IP3 p.Leu445Pro Likely pathogenic ★★ 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/mapk8ip3-p-val421ala (accessed [today's date]).

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