Is MAPK15 p.Arg496Trp (c.1486C>T) pathogenic?

MAPK15 p.Arg496Trp (c.1486C>T) is classified Uncertain significance in MAPK15 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-11). AlphaMissense: likely benign (0.1205); Ultra-rare (popmax 0.0467%, amr).

How common is MAPK15 p.Arg496Trp (c.1486C>T) in the general population?

MAPK15 p.Arg496Trp (c.1486C>T) is ultra-rare (popmax 0.0467%, amr) (gnomAD).

What do computational predictors say about MAPK15 p.Arg496Trp (c.1486C>T)?

AlphaMissense predicts likely benign (score 0.1205) — an in-silico prediction, not a clinical call.

MAPK15 p.Arg496Trp

c.1486C>T · rs200198011 · VCV2352889

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1205 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0467%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1205	likely benign
REVEL	0.395	indeterminate
SaProt	LLR -7.96	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.89	GERP -0.89, phastCons 0.41
Regional constraint	o/e 1.09	unconstrained · MANE · 5,870 bp · p 0.014 · regional, not allelic
Overall
CADD	22.5	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 0.0467% Admixed American · 28/59,994 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0286%

Overall 0.037% 596/1,612,358 alleles · ultra-rare exomes 561/1,460,106 · genomes 35/152,252 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.524%	191
Remaining individualsnot grpmax-eligible	0.0705%	1,419
Admixed Americangrpmax	0.0467%	2,143
European (non-Finnish)	0.0303%	3,296
Middle Eastern	0.0174%	5,734
South Asian	0.00659%	15,172
African / African-American	0.00267%	37,507
East Asian	0.00223%	44,862
Finnishnot grpmax-eligible	0.00159%	62,974

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg496Trp
Coding: c.1486C>T
MANE Select: NM_139021
dbSNP: rs200198011
Type: single nucleotide variant
Location: chr8:143722102 (GRCh38)
Gene constraint: LOEUF 1.344 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.56

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

Similar variants

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
MAPK15 p.Ala514Thr 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-arg496trp (accessed [today's date]).

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