Is MAPK15 p.Arg338Cys (c.1012C>T) pathogenic?

MAPK15 p.Arg338Cys (c.1012C>T) is classified Uncertain significance in MAPK15 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely benign (0.0977); Very rare (popmax 0.00936%, afr).

How common is MAPK15 p.Arg338Cys (c.1012C>T) in the general population?

MAPK15 p.Arg338Cys (c.1012C>T) is very rare (popmax 0.00936%, afr) (gnomAD).

What do computational predictors say about MAPK15 p.Arg338Cys (c.1012C>T)?

AlphaMissense predicts likely benign (score 0.0977) — an in-silico prediction, not a clinical call.

MAPK15 p.Arg338Cys

c.1012C>T · rs782338338 · VCV2380340

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00936%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0977	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -10.88	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.13	GERP -2.8
Regional constraint	o/e 1.09	unconstrained · MANE · 5,870 bp · p 0.014 · regional, not allelic
Overall
CADD	21.3	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 0.00936% African / African-American · 7/74,824 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00236% 38/1,610,874 alleles · very rare exomes 27/1,458,786 · genomes 11/152,088 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00936%	10,689
East Asian	0.00893%	11,203
Admixed American	0.00835%	11,975
European (non-Finnish)	0.0017%	58,941
Remaining individualsnot grpmax-eligible	0.0016%	62,332
South Asian	0.0011%	90,898

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.Arg338Cys
Coding: c.1012C>T
MANE Select: NM_139021
dbSNP: rs782338338
Type: single nucleotide variant
Location: chr8:143721094 (GRCh38)
Gene constraint: LOEUF 1.344 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.56
Residue 338: the 'requires for interaction with gabarap, map1lc3b and gabarapl1' region

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-arg338cys (accessed [today's date]).

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