Is MAP3K12 p.Glu855Ala (c.2564A>C) pathogenic?

MAP3K12 p.Glu855Ala (c.2564A>C) is classified Uncertain significance in MAP3K12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: likely benign (0.084); Ultra-rare (popmax 0.0426%, afr).

How common is MAP3K12 p.Glu855Ala (c.2564A>C) in the general population?

MAP3K12 p.Glu855Ala (c.2564A>C) is ultra-rare (popmax 0.0426%, afr) (gnomAD).

What do computational predictors say about MAP3K12 p.Glu855Ala (c.2564A>C)?

AlphaMissense predicts likely benign (score 0.084) — an in-silico prediction, not a clinical call.

MAP3K12 p.Glu855Ala

c.2564A>C · VCV3870149

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.084 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0426%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.084	likely benign
REVEL	0.172	moderately benign-leaning
SaProt	LLR -6.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.85 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.4	GERP 1.6, phastCons 0.87
Regional constraint	o/e 0.99	unconstrained · MANE · 2,240 bp · p 0.77 · regional, not allelic
Overall
CADD	15.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM E822A vs ClinVar E855A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0426% African / African-American · 32/75,046 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0271%

Overall 0.00223% 36/1,613,090 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0426%	2,345
Middle Eastern	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.0032%	31,224
Admixed American	0.00167%	60,010

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.Glu855Ala
Coding: c.2564A>C
MANE Select: NM_001193511
Type: single nucleotide variant
Location: chr12:53481957 (GRCh38)
Gene constraint: LOEUF 0.247 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.80 · 12 PDB
Residue 855: 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-glu855ala (accessed [today's date]).

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