ALDH9A1

Chr 1

aldehyde dehydrogenase 9 family member A1

Also known as: ALDH4, ALDH7, ALDH9, E3, TMABA-DH, TMABADH, TMABALDH

NCBI Gene: 223 ENSG00000143149 UniProt: P49189 OMIM: 602733

This enzyme catalyzes the oxidation of gamma-aminobutyraldehyde to GABA and converts gamma-trimethylaminobutyraldehyde to gamma-butyrobetaine in carnitine biosynthesis. Biallelic mutations cause autosomal recessive intellectual disability with seizures and hypotonia, typically presenting in infancy. The gene shows minimal constraint against loss-of-function variants in the population.

OMIM ResearchSummary from RefSeq, UniProt

This protein belongs to the aldehyde dehydrogenase family of proteins. It has a high activity for oxidation of gamma-aminobutyraldehyde and other amino aldehydes. The enzyme catalyzes the dehydrogenation of gamma-aminobutyraldehyde to gamma-aminobutyric acid (GABA). This isozyme is a tetramer of identical 54-kD subunits. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.14

Clinical Summary— ALDH9A1

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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

70 VUS of 89 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.14LOEUF

pLI 0.000

Z-score 1.01

OE 0.78 (0.55–1.14)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.42Z-score

OE missense 1.07 (0.97–1.17)

312 obs / 292.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.78 (0.55–1.14)

0≤0.351.4

Missense OE?1.07 (0.97–1.17)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 20 / 25.5Missense obs/exp: 312 / 292.0Syn Z: -0.86

This gene — mechanism propensity

0.7035th %ile

GOF

0.6345th %ile

LOF

0.3356th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

89 submitted variants in ClinVar

ClinVar

Classification Summary

VUS70

Likely Benign5

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	70	0	70
Likely Benign	3	2	5
Benign	0	0	0
Total	73	2	75

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap ALDH9A1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →