Is ADH4 p.Val209Leu (c.625G>T) pathogenic?

ADH4 p.Val209Leu (c.625G>T) is classified Uncertain significance in ADH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-30). AlphaMissense: likely pathogenic (0.6412); Very rare (popmax 0.000169%, nfe).

How common is ADH4 p.Val209Leu (c.625G>T) in the general population?

ADH4 p.Val209Leu (c.625G>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ADH4 p.Val209Leu (c.625G>T)?

AlphaMissense predicts likely pathogenic (score 0.6412) — an in-silico prediction, not a clinical call.

ADH4 p.Val209Leu

c.625G>T · rs771009134 · VCV3089012

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6412 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6412	likely pathogenic
REVEL	0.207	benign-leaning
SaProt	LLR -12.50	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.093	GERP 1.8, phastCons 0.002
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.41 · regional, not allelic
Overall
CADD	22.5	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 0.000169% European (non-Finnish) · 2/1,180,022 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,074 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.Val209Leu
Coding: c.625G>T
MANE Select: NM_000670
dbSNP: rs771009134
Type: single nucleotide variant
Location: chr4:99131722 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 98.23 · 1 PDB
Residue 209: an α-helix; a binding site

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.Ala72Val Uncertain significance ★ ⚠ same type
ADH4 p.Arg318Cys Uncertain significance ★ ⚠ same type
ADH4 p.Arg318Leu 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-val209leu (accessed [today's date]).

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