Is MAPK8IP3 p.Arg640Ser (c.1918C>A) pathogenic?

MAPK8IP3 p.Arg640Ser (c.1918C>A) is classified Uncertain significance in MAPK8IP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-20). AlphaMissense: likely pathogenic (0.8674); Very rare (popmax 0.00231%, eas).

How common is MAPK8IP3 p.Arg640Ser (c.1918C>A) in the general population?

MAPK8IP3 p.Arg640Ser (c.1918C>A) is very rare (popmax 0.00231%, eas) (gnomAD).

What do computational predictors say about MAPK8IP3 p.Arg640Ser (c.1918C>A)?

AlphaMissense predicts likely pathogenic (score 0.8674) — an in-silico prediction, not a clinical call.

MAPK8IP3 p.Arg640Ser

c.1918C>A · VCV3364197

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8674 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00231%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8674	likely pathogenic
REVEL	0.187	benign-leaning
SaProt	LLR -6.14	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.33	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 1.2	GERP -2.6, phastCons 0.52
Regional constraint	o/e 0.88	unconstrained · MANE · 5,099 bp · p 0.00099 · regional, not allelic
Overall
CADD	24.1	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 R639S vs ClinVar R640S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00231% East Asian · 1/43,284 alleles

Overall 0.000189% 3/1,583,162 alleles · very rare exomes 2/1,430,946 · genomes 1/152,216 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00231%	43,284
Admixed American	0.00175%	56,994
African / African-American	0.00135%	74,036

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.Arg640Ser
Coding: c.1918C>A
MANE Select: NM_001318852
Type: single nucleotide variant
Location: chr16:1763676 (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.Arg640Pro 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-arg640ser (accessed [today's date]).

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