Is ADH4 p.Ala72Val (c.215C>T) pathogenic?

ADH4 p.Ala72Val (c.215C>T) is classified Uncertain significance in ADH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-14). AlphaMissense: ambiguous (0.37); Very rare (popmax 0.00127%, nfe).

How common is ADH4 p.Ala72Val (c.215C>T) in the general population?

ADH4 p.Ala72Val (c.215C>T) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about ADH4 p.Ala72Val (c.215C>T)?

AlphaMissense predicts ambiguous (score 0.37) — an in-silico prediction, not a clinical call.

ADH4 p.Ala72Val

c.215C>T · rs756942645 · VCV2617910

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.37 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Computational evidence

Protein change
AlphaMissense	0.37	ambiguous
REVEL	0.321	indeterminate
SaProt	LLR -10.26	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.23	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.41 · regional, not allelic
Overall
CADD	22.7	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 0.00127% European (non-Finnish) · 15/1,179,990 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000929% 15/1,613,858 alleles · very rare

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: ADH4
Protein: p.Ala72Val
Coding: c.215C>T
MANE Select: NM_000670
dbSNP: rs756942645
Type: single nucleotide variant
Location: chr4:99141588 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 98.23 · 1 PDB
Residue 72: a β-strand

Full ADH4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADH4 p.Ala15Thr Uncertain significance ★ ⚠ same type
ADH4 p.Ala188Val Uncertain significance ★ ⚠ same type
ADH4 p.Ala222Thr Uncertain significance ★ ⚠ same type
ADH4 p.Ala290Thr Uncertain significance ★ ⚠ same type
ADH4 p.Ala62Pro Uncertain significance ★ ⚠ same type
ADH4 p.Arg318Cys Uncertain significance ★ ⚠ same type
ADH4 p.Arg318Leu Uncertain significance ★ ⚠ same type
ADH4 p.Arg375Gln 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/adh4-p-ala72val (accessed [today's date]).

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