Is MAPK8IP3 p.Ala558Val (c.1673C>T) pathogenic?

MAPK8IP3 p.Ala558Val (c.1673C>T) is classified Uncertain significance in MAPK8IP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: likely pathogenic (0.9541); Very rare (popmax 0.00273%, afr); Associated with Inborn genetic diseases.

What condition is associated with MAPK8IP3 p.Ala558Val (c.1673C>T)?

MAPK8IP3 p.Ala558Val (c.1673C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MAPK8IP3 p.Ala558Val (c.1673C>T) in the general population?

MAPK8IP3 p.Ala558Val (c.1673C>T) is very rare (popmax 0.00273%, afr) (gnomAD).

What do computational predictors say about MAPK8IP3 p.Ala558Val (c.1673C>T)?

AlphaMissense predicts likely pathogenic (score 0.9541) — an in-silico prediction, not a clinical call.

MAPK8IP3 p.Ala558Val

c.1673C>T · rs761016475 · VCV2240776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9541 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00273%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9541	likely pathogenic
REVEL	0.249	benign-leaning
SaProt	LLR -9.33	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 5,099 bp · p 0.00099 · regional, not allelic
Overall
CADD	24.7	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 A557V vs ClinVar A558V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00273% African / African-American · 2/73,296 alleles

Filtering AF 0.000453% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00017%

Overall 0.000451% 7/1,552,066 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00273%	36,648
European (non-Finnish)	0.000436%	229,430

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.Ala558Val
Coding: c.1673C>T
MANE Select: NM_001318852
dbSNP: rs761016475
Type: single nucleotide variant
Location: chr16:1762677 (GRCh38)
Gene constraint: LOEUF 0.407 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.19 · 5 PDB
Residue 558: the rh2 domain; a UniProt-annotated variant site (in nedba)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAPK8IP3 p.Arg579Cys Pathogenic/Likely pathogenic ★★ same condition
MAPK8IP3 c.1898+5G>A Uncertain significance ★★ same condition
MAPK8IP3 p.Ala883Thr Uncertain significance ★★ ⚠ same condition
MAPK8IP3 p.Arg1012Cys Uncertain significance ★★ ⚠ same condition
MAPK8IP3 p.Arg1187Gln Uncertain significance ★★ ⚠ same condition
MAPK8IP3 p.Arg308Cys Uncertain significance ★★ ⚠ same condition
MAPK8IP3 p.Arg310Trp Uncertain significance ★★ ⚠ same condition
MAPK8IP3 p.Arg612Cys Uncertain significance ★★ ⚠ 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/mapk8ip3-p-ala558val (accessed [today's date]).

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