Is ADH4 p.His69Arg (c.206A>G) pathogenic?

ADH4 p.His69Arg (c.206A>G) is classified Uncertain significance in ADH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-01). AlphaMissense: likely pathogenic (0.9503); Very rare (popmax 0.00229%, nfe).

How common is ADH4 p.His69Arg (c.206A>G) in the general population?

ADH4 p.His69Arg (c.206A>G) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about ADH4 p.His69Arg (c.206A>G)?

AlphaMissense predicts likely pathogenic (score 0.9503) — an in-silico prediction, not a clinical call.

ADH4 p.His69Arg

c.206A>G · rs745518809 · VCV2555225

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9503 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9503	likely pathogenic · top 7% in ADH4
REVEL	0.53	indeterminate
SaProt	LLR -13.33	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 5.7	GERP 1.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.41 · regional, not allelic
Overall
CADD	24.6	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00229% European (non-Finnish) · 27/1,180,018 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00186% 30/1,613,970 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)grpmax	0.00229%	43,704
African / African-American	0.00133%	74,940

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.His69Arg
Coding: c.206A>G
MANE Select: NM_000670
dbSNP: rs745518809
Type: single nucleotide variant
Location: chr4:99141597 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 98.23 · 1 PDB
Residue 69: 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-his69arg (accessed [today's date]).

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