Is ADH4 p.Pro87Arg (c.260C>G) pathogenic?

ADH4 p.Pro87Arg (c.260C>G) is classified Uncertain significance in ADH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: likely benign (0.1937); Very rare (popmax 0.00306%, nfe).

How common is ADH4 p.Pro87Arg (c.260C>G) in the general population?

ADH4 p.Pro87Arg (c.260C>G) is very rare (popmax 0.00306%, nfe) (gnomAD).

What do computational predictors say about ADH4 p.Pro87Arg (c.260C>G)?

AlphaMissense predicts likely benign (score 0.1937) — an in-silico prediction, not a clinical call.

ADH4 p.Pro87Arg

c.260C>G · rs376943095 · VCV2210437

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00306%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1937	likely benign
REVEL	0.313	indeterminate
SaProt	LLR -11.14	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.67 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.9	GERP 0.63, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.41 · regional, not allelic
Overall
CADD	24.8	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 0.00306% European (non-Finnish) · 36/1,176,480 alleles

Filtering AF 0.00224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00199%

Overall 0.00231% 37/1,604,538 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00306%	32,680
Remaining individualsnot grpmax-eligible	0.00161%	62,040

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.Pro87Arg
Coding: c.260C>G
MANE Select: NM_000670
dbSNP: rs376943095
Type: single nucleotide variant
Location: chr4:99141543 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 98.23 · 1 PDB

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-pro87arg (accessed [today's date]).

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