Is MAPK15 p.Leu99Pro (c.296T>C) pathogenic?

MAPK15 p.Leu99Pro (c.296T>C) is classified Uncertain significance in MAPK15 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: likely pathogenic (0.9546); Ultra-rare (popmax 0.0324%, nfe).

How common is MAPK15 p.Leu99Pro (c.296T>C) in the general population?

MAPK15 p.Leu99Pro (c.296T>C) is ultra-rare (popmax 0.0324%, nfe) (gnomAD).

What do computational predictors say about MAPK15 p.Leu99Pro (c.296T>C)?

AlphaMissense predicts likely pathogenic (score 0.9546) — an in-silico prediction, not a clinical call.

MAPK15 p.Leu99Pro

c.296T>C · rs368459044 · VCV2220862

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9546 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0324%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9546	likely pathogenic · top 2% in MAPK15
REVEL	0.701	pathogenic-leaning
SaProt	LLR -17.65	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 5,870 bp · p 0.014 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0324% European (non-Finnish) · 335/1,032,634 alleles

Filtering AF 0.0296% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0284%

Overall 0.0253% 347/1,370,716 alleles · ultra-rare exomes 327/1,247,952 · genomes 20/122,764 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0324%	3,082
Remaining individualsnot grpmax-eligible	0.0207%	4,833
Finnishnot grpmax-eligible	0.0024%	41,652
African / African-American	0.00168%	59,586

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.Leu99Pro
Coding: c.296T>C
MANE Select: NM_139021
dbSNP: rs368459044
Type: single nucleotide variant
Location: chr8:143718784 (GRCh38)
Gene constraint: LOEUF 1.344 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.56
Residue 99: 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-leu99pro (accessed [today's date]).

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