Is ADH4 p.His35Pro (c.104A>C) pathogenic?

ADH4 p.His35Pro (c.104A>C) is classified Uncertain significance in ADH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-15). AlphaMissense: ambiguous (0.5038); Ultra-rare (popmax 0.0501%, sas).

How common is ADH4 p.His35Pro (c.104A>C) in the general population?

ADH4 p.His35Pro (c.104A>C) is ultra-rare (popmax 0.0501%, sas) (gnomAD).

What do computational predictors say about ADH4 p.His35Pro (c.104A>C)?

AlphaMissense predicts ambiguous (score 0.5038) — an in-silico prediction, not a clinical call.

ADH4 p.His35Pro

c.104A>C · VCV4018541

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5038 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0501%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5038	ambiguous
REVEL	0.102	moderately benign-leaning
SaProt	LLR -12.35	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 0.23	GERP 0.5
Regional constraint	o/e 1.04	unconstrained · MANE · 20 kb · p 0.41 · regional, not allelic
Overall
CADD	19.57	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 0.0501% South Asian · 43/85,820 alleles

Filtering AF 0.0381% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.034%

Overall 0.00524% 83/1,584,876 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0501%	1,996
Remaining individualsnot grpmax-eligible	0.00493%	20,303
European (non-Finnish)	0.00308%	32,462
East Asian	0.00228%	43,928

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.His35Pro
Coding: c.104A>C
MANE Select: NM_000670
Type: single nucleotide variant
Location: chr4:99142695 (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-his35pro (accessed [today's date]).

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