Is ALDH2 p.Pro92Thr (c.274C>A) pathogenic?

ALDH2 p.Pro92Thr (c.274C>A) is classified Benign in ALDH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.1165); Low-frequency (popmax 1.59%, amr).

How common is ALDH2 p.Pro92Thr (c.274C>A) in the general population?

ALDH2 p.Pro92Thr (c.274C>A) is low-frequency (popmax 1.59%, amr) (gnomAD).

What do computational predictors say about ALDH2 p.Pro92Thr (c.274C>A)?

AlphaMissense predicts likely benign (score 0.1165) — an in-silico prediction, not a clinical call.

ALDH2 p.Pro92Thr

c.274C>A · rs201582342 · VCV779154

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1165 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.59%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1165	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -11.21	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 43 kb · p 1.7e-06 · regional, not allelic
Overall
CADD	22.4	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 1.59% Admixed American · 956/59,958 alleles

Filtering AF 1.51% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.48%

Overall 0.0624% 1,007/1,613,488 alleles · low-frequency

Ancestry group	Frequency	1 in
Admixed Americangrpmax	1.59%	63
Remaining individualsnot grpmax-eligible	0.0368%	2,717
African / African-American	0.0133%	7,507
South Asian	0.00989%	10,107
East Asian	0.00223%	44,870
European (non-Finnish)	0.000678%	147,461

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: ALDH2
Protein: p.Pro92Thr
Coding: c.274C>A
MANE Select: NM_000690
dbSNP: rs201582342
Type: single nucleotide variant
Location: chr12:111783212 (GRCh38)
Gene constraint: LOEUF 0.989 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.02 · 29 PDB
Residue 92: an α-helix

Full ALDH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALDH2 p.Pro92Ala Uncertain significance ★ ⚠ same residue
ALDH2 p.Ile41Val Likely benign ★★ same type
ALDH2 p.Thr244Met Likely benign ★★ ⚠ same type
ALDH2 p.Val304Met Benign ★★ same type
ALDH2 p.Arg114Gln Uncertain significance ★ ⚠ same type
ALDH2 p.Arg116Trp Uncertain significance ★ ⚠ same type
ALDH2 p.Arg268Cys Uncertain significance ★ ⚠ same type
ALDH2 p.Arg342Pro 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/aldh2-p-pro92thr (accessed [today's date]).

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