Is ADH7 p.Asp223Val (c.668A>T) pathogenic?

ADH7 p.Asp223Val (c.668A>T) is classified Uncertain significance in ADH7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-23). AlphaMissense: likely pathogenic (0.9754); Very rare (popmax 0.0011%, nfe).

How common is ADH7 p.Asp223Val (c.668A>T) in the general population?

ADH7 p.Asp223Val (c.668A>T) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about ADH7 p.Asp223Val (c.668A>T)?

AlphaMissense predicts likely pathogenic (score 0.9754) — an in-silico prediction, not a clinical call.

ADH7 p.Asp223Val

c.668A>T · VCV3273041

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9754 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9754	likely pathogenic · top 4% in ADH7
REVEL	0.609	indeterminate
SaProt	LLR -17.17	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 22 kb · p 0.00024 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 D235V vs ClinVar D223V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,179,906 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000868% 14/1,613,684 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0011%	90,762
South Asian	0.0011%	91,072

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.Asp223Val
Coding: c.668A>T
MANE Select: NM_000673
Type: single nucleotide variant
Location: chr4:99420690 (GRCh38)
Gene constraint: LOEUF 1.429 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.13 · 3 PDB
Residue 223: an α-helix

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

Similar variants

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
ADH7 p.Arg105Cys 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-asp223val (accessed [today's date]).

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