Is ADH7 p.Val66Met (c.196G>A) pathogenic?

ADH7 p.Val66Met (c.196G>A) is classified Uncertain significance in ADH7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-05). AlphaMissense: likely benign (0.2853); Ultra-rare (popmax 0.0133%, afr).

How common is ADH7 p.Val66Met (c.196G>A) in the general population?

ADH7 p.Val66Met (c.196G>A) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about ADH7 p.Val66Met (c.196G>A)?

AlphaMissense predicts likely benign (score 0.2853) — an in-silico prediction, not a clinical call.

ADH7 p.Val66Met

c.196G>A · rs776088318 · VCV2294071

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2853 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2853	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -5.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.4	GERP -3.5
Regional constraint	o/e 1.17	unconstrained · MANE · 22 kb · p 0.00024 · regional, not allelic
Overall
CADD	12.11	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 V78M vs ClinVar V66M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% African / African-American · 10/74,918 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.000682% 11/1,613,838 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,492
Admixed American	0.00167%	59,966

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: ADH7
Protein: p.Val66Met
Coding: c.196G>A
MANE Select: NM_000673
dbSNP: rs776088318
Type: single nucleotide variant
Location: chr4:99428555 (GRCh38)
Gene constraint: LOEUF 1.429 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.13 · 3 PDB
Residue 66: an α-helix

Full ADH7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADH7 p.Val66Gly Uncertain significance ★ ⚠ same residue
ADH7 p.Lys226Glu Benign ★★ ⚠ same type
ADH7 c.-18A>T Uncertain significance ★ ⚠ same type
ADH7 c.-4C>G Uncertain significance ★ ⚠ same type
ADH7 p.Ala13Ser Uncertain significance ★ ⚠ same type
ADH7 p.Ala278Ser Uncertain significance ★ ⚠ same type
ADH7 p.Ala278Thr Uncertain significance ★ ⚠ same type
ADH7 p.Ala298Val 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/adh7-p-val66met (accessed [today's date]).

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