Is MAPK8IP3 p.Pro595Ala (c.1783C>G) pathogenic?

MAPK8IP3 p.Pro595Ala (c.1783C>G) is classified Uncertain significance in MAPK8IP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-14). AlphaMissense: likely benign (0.0918); Very rare (popmax 0.0011%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MAPK8IP3 p.Pro595Ala (c.1783C>G)?

MAPK8IP3 p.Pro595Ala (c.1783C>G) is associated with Inborn genetic diseases (ClinVar).

How common is MAPK8IP3 p.Pro595Ala (c.1783C>G) in the general population?

MAPK8IP3 p.Pro595Ala (c.1783C>G) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about MAPK8IP3 p.Pro595Ala (c.1783C>G)?

AlphaMissense predicts likely benign (score 0.0918) — an in-silico prediction, not a clinical call.

MAPK8IP3 p.Pro595Ala

c.1783C>G · rs907527105 · VCV2473715

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0918 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0918	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -7.22	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 7.5	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 5,099 bp · p 0.00099 · regional, not allelic
Overall
CADD	22.4	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P594A vs ClinVar P595A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,179,994 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000806% 13/1,613,064 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.Pro595Ala
Coding: c.1783C>G
MANE Select: NM_001318852
dbSNP: rs907527105
Type: single nucleotide variant
Location: chr16:1762891 (GRCh38)
Gene constraint: LOEUF 0.407 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.19 · 5 PDB
Residue 595: 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.Pro595Thr Uncertain significance ★ ⚠ 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
MAPK8IP3 p.Arg308Cys Uncertain significance ★★ ⚠ same condition
MAPK8IP3 p.Arg310Trp 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-pro595ala (accessed [today's date]).

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