Is MAPK12 p.Arg189Trp (c.565C>T) pathogenic?

MAPK12 p.Arg189Trp (c.565C>T) is classified Uncertain significance in MAPK12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.9766); Ultra-rare (popmax 0.0706%, afr).

How common is MAPK12 p.Arg189Trp (c.565C>T) in the general population?

MAPK12 p.Arg189Trp (c.565C>T) is ultra-rare (popmax 0.0706%, afr) (gnomAD).

What do computational predictors say about MAPK12 p.Arg189Trp (c.565C>T)?

AlphaMissense predicts likely pathogenic (score 0.9766) — an in-silico prediction, not a clinical call.

MAPK12 p.Arg189Trp

c.565C>T · rs149914576 · VCV2515443

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9766 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0706%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9766	likely pathogenic
REVEL	0.369	indeterminate
SaProt	LLR -15.63	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.2	GERP -2.4, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 8,105 bp · p 0.021 · regional, not allelic
Overall
CADD	29.5	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 0.0706% African / African-American · 53/75,046 alleles

Filtering AF 0.0554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.05%

Overall 0.00614% 99/1,612,772 alleles · ultra-rare exomes 64/1,460,448 · genomes 35/152,324 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0706%	1,416
South Asian	0.0263%	3,795
Remaining individualsnot grpmax-eligible	0.0112%	8,926
Admixed American	0.00333%	30,006
European (non-Finnish)	0.0011%	90,764

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: MAPK12
Protein: p.Arg189Trp
Coding: c.565C>T
MANE Select: NM_002969
dbSNP: rs149914576
Type: single nucleotide variant
Location: chr22:50256139 (GRCh38)
Gene constraint: LOEUF 1.387 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.33 · 4 PDB
Residue 189: the protein kinase domain; an α-helix

Full MAPK12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPK12 p.Arg189Gln Uncertain significance ★ ⚠ same residue
MAPK12 p.Ala146Thr Uncertain significance ★ ⚠ same type
MAPK12 p.Ala175Val Uncertain significance ★ ⚠ same type
MAPK12 p.Ala296Thr Uncertain significance ★ ⚠ same type
MAPK12 p.Arg129Trp Uncertain significance ★ same type
MAPK12 p.Arg192Gln Uncertain significance ★ ⚠ same type
MAPK12 p.Arg192Trp Uncertain significance ★ ⚠ same type
MAPK12 p.Arg252Trp 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/mapk12-p-arg189trp (accessed [today's date]).

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