Is MAP3K12 p.Val346Ile (c.1036G>A) pathogenic?

MAP3K12 p.Val346Ile (c.1036G>A) is classified Uncertain significance in MAP3K12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: ambiguous (0.5099); Very rare (popmax 0.00333%, amr).

How common is MAP3K12 p.Val346Ile (c.1036G>A) in the general population?

MAP3K12 p.Val346Ile (c.1036G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about MAP3K12 p.Val346Ile (c.1036G>A)?

AlphaMissense predicts ambiguous (score 0.5099) — an in-silico prediction, not a clinical call.

MAP3K12 p.Val346Ile

c.1036G>A · VCV4103229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5099 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Computational evidence

Protein change
AlphaMissense	0.5099	ambiguous
REVEL	0.369	indeterminate
SaProt	LLR -6.91	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.94, phastCons 1
Regional constraint	o/e 0.15	constrained · MANE · 1,004 bp · p 3.9e-23 · regional, not allelic
Overall
CADD	29.1	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 V313I vs ClinVar V346I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,986 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.0013% 21/1,613,964 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,993
Remaining individualsnot grpmax-eligible	0.0032%	31,242
East Asian	0.00223%	44,896
European (non-Finnish)	0.00127%	78,666
South Asian	0.0011%	91,082

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.Val346Ile
Coding: c.1036G>A
MANE Select: NM_001193511
Type: single nucleotide variant
Location: chr12:53485159 (GRCh38)
Gene constraint: LOEUF 0.247 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.80 · 12 PDB
Residue 346: the protein kinase domain; an α-helix

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-val346ile (accessed [today's date]).

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