Is ADH1B p.Pro92Ser (c.274C>T) pathogenic?

ADH1B p.Pro92Ser (c.274C>T) is classified Uncertain significance in ADH1B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-22). AlphaMissense: ambiguous (0.4618); Very rare (popmax 0.005%, amr).

How common is ADH1B p.Pro92Ser (c.274C>T) in the general population?

ADH1B p.Pro92Ser (c.274C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about ADH1B p.Pro92Ser (c.274C>T)?

AlphaMissense predicts ambiguous (score 0.4618) — an in-silico prediction, not a clinical call.

ADH1B p.Pro92Ser

c.274C>T · rs1230758917 · VCV3088854

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4618 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4618	ambiguous
REVEL	0.273	benign-leaning
SaProt	LLR -13.34	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.6	GERP 0.79, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,404 bp · p 0.59 · regional, not allelic
Overall
CADD	23.6	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 0.005% Admixed American · 3/59,952 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000434% 7/1,613,886 alleles · very rare exomes 4/1,461,812 · genomes 3/152,074 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,984
Remaining individualsnot grpmax-eligible	0.0048%	20,825
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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: ADH1B
Protein: p.Pro92Ser
Coding: c.274C>T
MANE Select: NM_000668
dbSNP: rs1230758917
Type: single nucleotide variant
Location: chr4:99316288 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.86 · 9 PDB
Residue 92: a β-strand

Full ADH1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADH1B p.Pro92Leu Uncertain significance ★ ⚠ same residue
ADH1B p.Ala222= Benign ★★ same type
ADH1B p.Ser165= Benign ★★ same type
ADH1B p.Trp16Arg Benign ★★ same type
ADH1B p.Val204= Benign ★★ same type
ADH1B p.Ala164Ser Uncertain significance ★ ⚠ same type
ADH1B p.Ala222Val Uncertain significance ★ ⚠ same type
ADH1B p.Ala238Val 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/adh1b-p-pro92ser (accessed [today's date]).

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