ALDH5A1

Chr 6

aldehyde dehydrogenase 5 family member A1

Also known as: SSADH, SSDH

NCBI Gene: 7915 ENSG00000112294 UniProt: P51649

This mitochondrial NAD(+)-dependent enzyme catalyzes one step in the degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Mutations cause succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyricaciduria), a rare autosomal recessive inborn error of GABA metabolism that leads to accumulation of GHB in physiologic fluids. The gene shows very low constraint against loss-of-function variants (pLI near zero), which is consistent with its autosomal recessive inheritance pattern.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This protein belongs to the aldehyde dehydrogenase family of proteins. This gene encodes a mitochondrial NAD(+)-dependent succinic semialdehyde dehydrogenase. A deficiency of this enzyme, known as 4-hydroxybutyricaciduria, is a rare inborn error in the metabolism of the neurotransmitter 4-aminobutyric acid (GABA). In response to the defect, physiologic fluids from patients accumulate GHB, a compound with numerous neuromodulatory properties. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.94

Clinical Summary— ALDH5A1

🧬

Gene-Disease Validity (ClinGen)

succinic semialdehyde dehydrogenase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

155 unique Pathogenic / Likely Pathogenic· 334 VUS of 910 total submissions

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — ALDH5A1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.94LOEUF

pLI 0.000

Z-score 1.79

OE 0.60 (0.40–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.73Z-score

OE missense 0.88 (0.79–0.97)

254 obs / 289.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.60 (0.40–0.94)

0≤0.351.4

Missense OE?0.88 (0.79–0.97)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 14 / 23.4Missense obs/exp: 254 / 289.1Syn Z: 0.54

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveALDH5A1-related succinate semialdehyde dehydrogenase deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.75top 25%

GOF

0.6444th %ile

LOF

0.3066th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

910 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic86

Likely Pathogenic69

VUS334

Likely Benign281

Benign72

Conflicting51

Pathogenic

Likely Pathogenic

334

VUS

281

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	63	18	4	1	86
Likely Pathogenic	23	44	2	0	69
VUS	4	266	61	3	334
Likely Benign	0	7	111	163	281
Benign	0	4	65	3	72
Conflicting	—				51
Total	90	339	243	170	893

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap ALDH5A1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →