Is MAPK12 p.Arg192Trp (c.574C>T) pathogenic?

MAPK12 p.Arg192Trp (c.574C>T) is classified Uncertain significance in MAPK12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely pathogenic (0.9867); Rare (popmax 0.117%, afr).

How common is MAPK12 p.Arg192Trp (c.574C>T) in the general population?

MAPK12 p.Arg192Trp (c.574C>T) is rare (popmax 0.117%, afr) (gnomAD).

What do computational predictors say about MAPK12 p.Arg192Trp (c.574C>T)?

AlphaMissense predicts likely pathogenic (score 0.9867) — an in-silico prediction, not a clinical call.

MAPK12 p.Arg192Trp

c.574C>T · VCV4103729

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9867 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.117%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9867	likely pathogenic
REVEL	0.425	indeterminate
SaProt	LLR -15.68	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 5	GERP -0.82, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 8,105 bp · p 0.021 · regional, not allelic
Overall
CADD	32.0	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 0.117% African / African-American · 88/74,924 alleles

Filtering AF 0.0976% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0902%

Overall 0.00651% 105/1,612,616 alleles · rare exomes 54/1,460,418 · genomes 51/152,198 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.117%	851
Remaining individualsnot grpmax-eligible	0.00801%	12,492
Admixed American	0.00667%	14,997
South Asian	0.0011%	91,084
European (non-Finnish)	0.000593%	168,560

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.Arg192Trp
Coding: c.574C>T
MANE Select: NM_002969
Type: single nucleotide variant
Location: chr22:50256130 (GRCh38)
Gene constraint: LOEUF 1.387 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.33 · 4 PDB
Residue 192: the protein kinase domain

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

Similar variants

MAPK12 p.Arg192Gln 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.Arg189Gln Uncertain significance ★ ⚠ same type
MAPK12 p.Arg189Trp 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-arg192trp (accessed [today's date]).

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