Is MAPK8IP3 p.Pro588Ala (c.1762C>G) pathogenic?

MAPK8IP3 p.Pro588Ala (c.1762C>G) is classified Likely benign in MAPK8IP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-30). AlphaMissense: likely benign (0.0855); Ultra-rare (popmax 0.0227%, afr); Associated with Inborn genetic diseases.

What condition is associated with MAPK8IP3 p.Pro588Ala (c.1762C>G)?

MAPK8IP3 p.Pro588Ala (c.1762C>G) is associated with Inborn genetic diseases (ClinVar).

How common is MAPK8IP3 p.Pro588Ala (c.1762C>G) in the general population?

MAPK8IP3 p.Pro588Ala (c.1762C>G) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about MAPK8IP3 p.Pro588Ala (c.1762C>G)?

AlphaMissense predicts likely benign (score 0.0855) — an in-silico prediction, not a clinical call.

MAPK8IP3 p.Pro588Ala

c.1762C>G · rs573495601 · VCV3025899

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0855 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0855	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -6.58	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 5.8	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 5,099 bp · p 0.00099 · regional, not allelic
Overall
CADD	22.6	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 P587A vs ClinVar P588A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0227% African / African-American · 17/75,050 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.0026% 42/1,613,240 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,415
Remaining individualsnot grpmax-eligible	0.0048%	20,829
East Asian	0.00446%	22,438
Admixed American	0.00333%	30,013
Finnishnot grpmax-eligible	0.00158%	63,180
European (non-Finnish)	0.00136%	73,748
South Asian	0.0011%	91,080

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.Pro588Ala
Coding: c.1762C>G
MANE Select: NM_001318852
dbSNP: rs573495601
Type: single nucleotide variant
Location: chr16:1762870 (GRCh38)
Gene constraint: LOEUF 0.407 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.19 · 5 PDB
Residue 588: 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.Pro588His Uncertain significance ★ ⚠ same residue
MAPK8IP3 p.Pro588Ser Uncertain significance ★ ⚠ same residue
MAPK8IP3 p.Pro588= Likely benign ★ same residue
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

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-pro588ala (accessed [today's date]).

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