ALDH3A1

Chr 17

aldehyde dehydrogenase 3 family member A1

Also known as: ALDH3, ALDHIII

NCBI Gene: 218 ENSG00000108602 UniProt: P30838 OMIM: 100660

The enzyme oxidizes aromatic and medium-chain aldehydes to corresponding acids and comprises about 50% of corneal epithelial soluble proteins, playing a role in protecting the cornea from UV-induced oxidative damage. Biallelic mutations cause autosomal recessive microphthalmia with coloboma and other eye abnormalities. The gene shows low constraint against loss-of-function variants (pLI near zero), consistent with recessive inheritance requiring biallelic mutations for disease.

OMIM ResearchSummary from RefSeq, UniProt

Aldehyde dehydrogenases oxidize various aldehydes to the corresponding acids. They are involved in the detoxification of alcohol-derived acetaldehyde and in the metabolism of corticosteroids, biogenic amines, neurotransmitters, and lipid peroxidation. The enzyme encoded by this gene forms a cytoplasmic homodimer that preferentially oxidizes aromatic and medium-chain (6 carbons or more) saturated and unsaturated aldehyde substrates. It is thought to promote resistance to UV and 4-hydroxy-2-nonenal-induced oxidative damage in the cornea. The gene is located within the Smith-Magenis syndrome region on chromosome 17. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.53

Clinical Summary— ALDH3A1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 37 VUS of 57 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.53LOEUF

pLI 0.000

Z-score -0.40

OE 1.09 (0.79–1.53)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.30Z-score

OE missense 0.95 (0.86–1.05)

273 obs / 287.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.09 (0.79–1.53)

0≤0.351.4

Missense OE?0.95 (0.86–1.05)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 24 / 22.0Missense obs/exp: 273 / 287.1Syn Z: -0.58

This gene — mechanism propensity

0.7327th %ile

GOF

0.6639th %ile

LOF

0.2874th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

57 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS37

Likely Benign4

Benign5

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	1	0	1
VUS	37	0	37
Likely Benign	3	1	4
Benign	1	4	5
Total	42	5	47

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

98 pathogenic / likely-pathogenic (of 114) ClinVar copy-number / structural variants overlap ALDH3A1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →