Is MAPK15 p.Arg213Pro (c.638G>C) pathogenic?

MAPK15 p.Arg213Pro (c.638G>C) is classified Uncertain significance in MAPK15 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-15). AlphaMissense: ambiguous (0.5159); Very rare (popmax 0.00223%, eas).

How common is MAPK15 p.Arg213Pro (c.638G>C) in the general population?

MAPK15 p.Arg213Pro (c.638G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about MAPK15 p.Arg213Pro (c.638G>C)?

AlphaMissense predicts ambiguous (score 0.5159) — an in-silico prediction, not a clinical call.

MAPK15 p.Arg213Pro

c.638G>C · VCV3293212

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5159 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5159	ambiguous
REVEL	0.141	moderately benign-leaning
SaProt	LLR -13.20	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.6	GERP -3.7, phastCons 0.098
Regional constraint	o/e 1.09	unconstrained · MANE · 5,870 bp · p 0.014 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,836 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,611,274 alleles · very rare exomes 3/1,459,086 · genomes 1/152,188 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,836
African / African-American	0.00134%	74,818
European (non-Finnish)	0.00017%	589,466

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: MAPK15
Protein: p.Arg213Pro
Coding: c.638G>C
MANE Select: NM_139021
Type: single nucleotide variant
Location: chr8:143719399 (GRCh38)
Gene constraint: LOEUF 1.344 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.56
Residue 213: the protein kinase domain

Full MAPK15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPK15 p.Arg213Gln Uncertain significance ★ ⚠ same residue
MAPK15 p.Arg213Leu Uncertain significance ★ ⚠ same residue
MAPK15 p.Arg496Trp Uncertain significance ★★ ⚠ same type
MAPK15 p.Ser192Ter Likely benign ★★ same type
MAPK15 p.Ala179Thr Uncertain significance ★ ⚠ same type
MAPK15 p.Ala251Val Uncertain significance ★ ⚠ same type
MAPK15 p.Ala295Thr Uncertain significance ★ ⚠ same type
MAPK15 p.Ala40Val Uncertain significance ★ ⚠ 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/mapk15-p-arg213pro (accessed [today's date]).

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