Is MAPK12 p.Pro246Leu (c.737C>T) pathogenic?

MAPK12 p.Pro246Leu (c.737C>T) is classified Uncertain significance in MAPK12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-07). AlphaMissense: likely benign (0.1918); Ultra-rare (popmax 0.0108%, nfe).

How common is MAPK12 p.Pro246Leu (c.737C>T) in the general population?

MAPK12 p.Pro246Leu (c.737C>T) is ultra-rare (popmax 0.0108%, nfe) (gnomAD).

What do computational predictors say about MAPK12 p.Pro246Leu (c.737C>T)?

AlphaMissense predicts likely benign (score 0.1918) — an in-silico prediction, not a clinical call.

MAPK12 p.Pro246Leu

c.737C>T · VCV3870419

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1918 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0108%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1918	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -12.32	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 8.4	GERP -0.96, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 8,105 bp · p 0.021 · regional, not allelic
Overall
CADD	22.9	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 0.0108% European (non-Finnish) · 111/1,029,742 alleles

Filtering AF 0.00915% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00852%

Overall 0.00976% 133/1,362,760 alleles · ultra-rare exomes 124/1,232,138 · genomes 9/130,622 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0298%	3,357
European (non-Finnish)grpmax	0.0108%	9,277
East Asian	0.00887%	11,277
Admixed American	0.00407%	24,588
Finnishnot grpmax-eligible	0.00262%	38,236
South Asian	0.00228%	43,951
African / African-American	0.00162%	61,716

Remaining individuals 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: MAPK12
Protein: p.Pro246Leu
Coding: c.737C>T
MANE Select: NM_002969
Type: single nucleotide variant
Location: chr22:50255649 (GRCh38)
Gene constraint: LOEUF 1.387 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.33 · 4 PDB
Residue 246: 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.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.Arg192Gln Uncertain significance ★ ⚠ same type
MAPK12 p.Arg192Trp 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-pro246leu (accessed [today's date]).

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