Is ADH5 p.Val294Ile (c.880G>A) pathogenic?

ADH5 p.Val294Ile (c.880G>A) is classified Uncertain significance in ADH5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: likely benign (0.213); Ultra-rare (popmax 0.0494%, mid).

How common is ADH5 p.Val294Ile (c.880G>A) in the general population?

ADH5 p.Val294Ile (c.880G>A) is ultra-rare (popmax 0.0494%, mid) (gnomAD).

What do computational predictors say about ADH5 p.Val294Ile (c.880G>A)?

AlphaMissense predicts likely benign (score 0.213) — an in-silico prediction, not a clinical call.

ADH5 p.Val294Ile

c.880G>A · rs750535620 · VCV2511029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.213 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.213	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -11.77	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 16 kb · p 5.5e-07 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0494% Middle Eastern · 3/6,078 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.00254% 41/1,613,260 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0494%	2,026
Remaining individualsnot grpmax-eligible	0.00641%	15,607
Admixed American	0.005%	19,989
South Asian	0.0033%	30,337
European (non-Finnish)	0.00229%	43,686
African / African-American	0.00134%	74,898

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: ADH5
Protein: p.Val294Ile
Coding: c.880G>A
MANE Select: NM_000671
dbSNP: rs750535620
Type: single nucleotide variant
Location: chr4:99074995 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 98.13 · 10 PDB

Full ADH5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADH5 p.Thr178= Likely benign ★★ same type
ADH5 c.114+1G>A Pathogenic ★ same type
ADH5 p.Ala278Pro Pathogenic ★ same type
ADH5 p.Arg218Leu Uncertain significance ★ same type
ADH5 p.Arg36Gln Uncertain significance ★ ⚠ same type
ADH5 p.Asn225Ser Uncertain significance ★ ⚠ same type
ADH5 p.Asn3Lys Uncertain significance ★ ⚠ same type
ADH5 p.Asp223Asn 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/adh5-p-val294ile (accessed [today's date]).

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