Is MAPK15 p.Pro235Leu (c.704C>T) pathogenic?

MAPK15 p.Pro235Leu (c.704C>T) is classified Uncertain significance in MAPK15 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-10). AlphaMissense: likely benign (0.1079); Ultra-rare (popmax 0.0187%, mid).

How common is MAPK15 p.Pro235Leu (c.704C>T) in the general population?

MAPK15 p.Pro235Leu (c.704C>T) is ultra-rare (popmax 0.0187%, mid) (gnomAD).

What do computational predictors say about MAPK15 p.Pro235Leu (c.704C>T)?

AlphaMissense predicts likely benign (score 0.1079) — an in-silico prediction, not a clinical call.

MAPK15 p.Pro235Leu

c.704C>T · rs537644016 · VCV2600817

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1079 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1079	likely benign
REVEL	0.243	benign-leaning
SaProt	LLR -9.65	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.6	GERP 0.9, phastCons 0.95
Regional constraint	o/e 1.09	unconstrained · MANE · 5,870 bp · p 0.014 · regional, not allelic
Overall
CADD	20.7	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% Middle Eastern · 1/5,356 alleles

Filtering AF 0.00937% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00741%

Overall 0.00112% 18/1,608,170 alleles · ultra-rare exomes 18/1,455,804 · genomes 0/152,366 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0187%	5,356
South Asian	0.0155%	6,454
Remaining individualsnot grpmax-eligible	0.00322%	31,086
European (non-Finnish)	8.49e-05%	1,178,387

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.Pro235Leu
Coding: c.704C>T
MANE Select: NM_139021
dbSNP: rs537644016
Type: single nucleotide variant
Location: chr8:143719465 (GRCh38)
Gene constraint: LOEUF 1.344 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.56
Residue 235: the protein kinase domain

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

Similar variants

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
MAPK15 p.Ala436Ser Uncertain significance ★ ⚠ same type
MAPK15 p.Ala436Val 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-pro235leu (accessed [today's date]).

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