Is MAP3K12 p.Val759Ala (c.2276T>C) pathogenic?

MAP3K12 p.Val759Ala (c.2276T>C) is classified Uncertain significance in MAP3K12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-23). AlphaMissense: likely pathogenic (0.7549); Very rare (popmax 0.00144%, nfe).

How common is MAP3K12 p.Val759Ala (c.2276T>C) in the general population?

MAP3K12 p.Val759Ala (c.2276T>C) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about MAP3K12 p.Val759Ala (c.2276T>C)?

AlphaMissense predicts likely pathogenic (score 0.7549) — an in-silico prediction, not a clinical call.

MAP3K12 p.Val759Ala

c.2276T>C · VCV4103227

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7549 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7549	likely pathogenic
REVEL	0.197	benign-leaning
SaProt	LLR -5.66	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 2,240 bp · p 0.77 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V726A vs ClinVar V759A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00144% European (non-Finnish) · 17/1,179,372 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00118% 19/1,611,216 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,223
European (non-Finnish)grpmax	0.00144%	69,375

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: MAP3K12
Protein: p.Val759Ala
Coding: c.2276T>C
MANE Select: NM_001193511
Type: single nucleotide variant
Location: chr12:53482332 (GRCh38)
Gene constraint: LOEUF 0.247 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.80 · 12 PDB
Residue 759: the 'disordered' region

Full MAP3K12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K12 p.Gly661Arg Uncertain significance ★★ ⚠ same type
MAP3K12 p.Gly673Ser Benign ★★ same type
MAP3K12 p.Ala671Asp Uncertain significance ★ ⚠ same type
MAP3K12 p.Arg106Gln Uncertain significance ★ ⚠ same type
MAP3K12 p.Arg176Cys Uncertain significance ★ ⚠ same type
MAP3K12 p.Arg236Trp Uncertain significance ★ ⚠ same type
MAP3K12 p.Arg488Lys Uncertain significance ★ ⚠ same type
MAP3K12 p.Arg572Gln 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/map3k12-p-val759ala (accessed [today's date]).

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