Is ADH4 p.Arg318Cys (c.952C>T) pathogenic?

ADH4 p.Arg318Cys (c.952C>T) is classified Uncertain significance in ADH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-21). AlphaMissense: ambiguous (0.4163); Very rare (popmax 0.00447%, eas).

How common is ADH4 p.Arg318Cys (c.952C>T) in the general population?

ADH4 p.Arg318Cys (c.952C>T) is very rare (popmax 0.00447%, eas) (gnomAD).

What do computational predictors say about ADH4 p.Arg318Cys (c.952C>T)?

AlphaMissense predicts ambiguous (score 0.4163) — an in-silico prediction, not a clinical call.

ADH4 p.Arg318Cys

c.952C>T · rs781087602 · VCV3089031

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4163 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4163	ambiguous
REVEL	0.217	benign-leaning
SaProt	LLR -14.21	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.41 · regional, not allelic
Overall
CADD	26.1	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 0.00447% East Asian · 2/44,700 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000896%

Overall 0.00106% 17/1,609,720 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00447%	22,350
South Asian	0.00442%	22,599
Admixed American	0.00335%	29,834
Remaining individualsnot grpmax-eligible	0.0016%	62,306
European (non-Finnish)	0.000679%	147,248

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.Arg318Cys
Coding: c.952C>T
MANE Select: NM_000670
dbSNP: rs781087602
Type: single nucleotide variant
Location: chr4:99127236 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 98.23 · 1 PDB
Residue 318: a UniProt-annotated variant site (in); a β-strand

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

Similar variants

ADH4 p.Arg318Leu Uncertain significance ★ ⚠ same residue
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.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-arg318cys (accessed [today's date]).

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