ALDH18A1

Chr 10ADAR

aldehyde dehydrogenase 18 family member A1

Also known as: ADCL3, ARCL3A, GSAS, P5CS, PYCS, SPG9, SPG9A, SPG9B

NCBI Gene: 5832 ENSG00000059573 UniProt: P54886 OMIM: 138250

The encoded bifunctional enzyme converts glutamate to glutamate 5-semialdehyde, a critical step in the biosynthesis of proline, ornithine and arginine. Mutations cause cutis laxa (both autosomal dominant and recessive forms) and hereditary spastic paraplegia (types 9A and 9B), with associated features including hyperammonemia, cataracts, and connective tissue abnormalities. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.52) and exhibits both autosomal dominant and recessive inheritance patterns depending on the specific condition.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the aldehyde dehydrogenase family and encodes a bifunctional ATP- and NADPH-dependent mitochondrial enzyme with both gamma-glutamyl kinase and gamma-glutamyl phosphate reductase activities. The encoded protein catalyzes the reduction of glutamate to delta1-pyrroline-5-carboxylate, a critical step in the de novo biosynthesis of proline, ornithine and arginine. Mutations in this gene lead to hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia and may be associated with neurodegeneration, cataracts and connective tissue diseases. Alternatively spliced transcript variants, encoding different isoforms, have been described for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.524 OMIM phenotypes

Clinical Summary— ALDH18A1

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Gene-Disease Validity (ClinGen)

P5CS deficiency · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.001

Z-score 3.94

OE 0.33 (0.21–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.97Z-score

OE missense 0.74 (0.67–0.81)

325 obs / 441.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.21–0.52)

0≤0.351.4

Missense OE?0.74 (0.67–0.81)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 13 / 39.8Missense obs/exp: 325 / 441.2Syn Z: 0.48

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedALDH18A1-related spastic paraplegia (biallelic)OTHERAR

definitiveALDH18A1-related cutis laxaGOFAD

definitiveALDH18A1-related spastic paraplegia (monoallelic)DNAD

definitiveALDH18A1-related developmental disorder-joint hypermobility-skin laxity with or without metabolic abnormalitiesLOFAR

This gene — mechanism propensity

0.7326th %ile

GOF

0.5759th %ile

LOF

0.3843th %ile

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

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNImaging in cutis laxa syndrome caused by a dominant negative ALDH18A1 mutation, with hypotheses for intracranial vascular tortuosity and wide perivascular spaces.1

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

References