Is MAP3K7 p.Val76Ile (c.226G>A) pathogenic?

MAP3K7 p.Val76Ile (c.226G>A) is classified Uncertain significance in MAP3K7 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-26). AlphaMissense: likely benign (0.2427); Very rare (popmax 0.00179%, amr).

How common is MAP3K7 p.Val76Ile (c.226G>A) in the general population?

MAP3K7 p.Val76Ile (c.226G>A) is very rare (popmax 0.00179%, amr) (gnomAD).

What do computational predictors say about MAP3K7 p.Val76Ile (c.226G>A)?

AlphaMissense predicts likely benign (score 0.2427) — an in-silico prediction, not a clinical call.

MAP3K7 p.Val76Ile

c.226G>A · rs762124152 · VCV1302191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2427 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00179%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2427	likely benign
REVEL	0.313	indeterminate
SaProt	LLR -6.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.36	constrained · MANE · 35 kb · p 4.4e-26 · regional, not allelic
Overall
CADD	22.7	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00179% Admixed American · 1/55,880 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000381% 6/1,576,750 alleles · very rare exomes 4/1,424,732 · genomes 2/152,018 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00179%	55,880
Remaining individualsnot grpmax-eligible	0.00164%	60,844
African / African-American	0.00137%	73,218
South Asian	0.00115%	86,676
European (non-Finnish)	0.000173%	579,049

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: MAP3K7
Protein: p.Val76Ile
Coding: c.226G>A
MANE Select: NM_145331
dbSNP: rs762124152
Type: single nucleotide variant
Location: chr6:90571702 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.27 · 25 PDB
Residue 76: the protein kinase domain; the 'interaction with mapk8ip1' region; an α-helix

Full MAP3K7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K7 p.Arg274Cys Pathogenic/Likely pathogenic ★★ same type
MAP3K7 p.Gly110Ser Pathogenic/Likely pathogenic ★★ same type
MAP3K7 p.Pro512Leu Pathogenic ★★ same type
MAP3K7 p.Ala313Thr Uncertain significance ★★ ⚠ same type
MAP3K7 p.Ala400Thr Uncertain significance ★★ ⚠ same type
MAP3K7 p.Ala6Thr Uncertain significance ★★ ⚠ same type
MAP3K7 p.Arg289Gln Uncertain significance ★★ ⚠ same type
MAP3K7 p.Arg347His 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/map3k7-p-val76ile (accessed [today's date]).

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