Is MAPK8IP3 p.Arg640Pro (c.1919G>C) pathogenic?

MAPK8IP3 p.Arg640Pro (c.1919G>C) is classified Uncertain significance in MAPK8IP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-26). AlphaMissense: likely pathogenic (0.8315); Absent from gnomAD v4.1.

How common is MAPK8IP3 p.Arg640Pro (c.1919G>C) in the general population?

MAPK8IP3 p.Arg640Pro (c.1919G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAPK8IP3 p.Arg640Pro (c.1919G>C)?

AlphaMissense predicts likely pathogenic (score 0.8315) — an in-silico prediction, not a clinical call.

MAPK8IP3 p.Arg640Pro

c.1919G>C · VCV3363525

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8315 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8315	likely pathogenic
REVEL	0.359	indeterminate
SaProt	LLR -7.08	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 5,099 bp · p 0.00099 · regional, not allelic
Overall
CADD	26.1	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 R639P vs ClinVar R640P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAPK8IP3
Protein: p.Arg640Pro
Coding: c.1919G>C
MANE Select: NM_001318852
Type: single nucleotide variant
Location: chr16:1763677 (GRCh38)
Gene constraint: LOEUF 0.407 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.19 · 5 PDB
Residue 639 UniProt numbering: a UniProt-annotated variant site (in nedba)

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

Similar variants

MAPK8IP3 p.Arg640Cys Uncertain significance ★ ⚠ same residue
MAPK8IP3 p.Arg640Ser Uncertain significance ★ ⚠ same residue
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-arg640pro (accessed [today's date]).

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