Is ALDH2 p.Pro188= (c.564G>A) pathogenic?

ALDH2 p.Pro188= (c.564G>A) is classified Benign in ALDH2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-29). Ultra-rare (popmax 0.0165%, mid); Associated with ALDH2-related disorder.

What condition is associated with ALDH2 p.Pro188= (c.564G>A)?

ALDH2 p.Pro188= (c.564G>A) is associated with ALDH2-related disorder (ClinVar).

How common is ALDH2 p.Pro188= (c.564G>A) in the general population?

ALDH2 p.Pro188= (c.564G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

ALDH2 p.Pro188=

c.564G>A · rs58280059 · VCV3035849

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

ALDH2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -3.9
Overall
CADD	0.267	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.0113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0107%

Overall 0.0489% 790/1,614,090 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.86%	54
Remaining individualsnot grpmax-eligible	0.11%	906
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.016%	6,252
European (non-Finnish)	0.0131%	7,662
East Asian	0.00223%	44,868
South Asian	0.0011%	91,074

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro188=
Coding: c.564G>A
MANE Select: NM_000690
dbSNP: rs58280059
Type: single nucleotide variant
Location: chr12:111790445 (GRCh38)
Gene constraint: LOEUF 0.989 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.02 · 29 PDB
Residue 188: an α-helix

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

Disease context

ALDH2-related disorder

Similar variants

ALDH2 p.Pro188Leu Uncertain significance ★ ⚠ same residue
ALDH2 p.Ile41Val Likely benign ★★ same type
ALDH2 p.Pro92Thr 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

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-pro188 (accessed [today's date]).

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