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.

GeneReviews 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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Cutis laxa, autosomal dominant 3MIM #616603

Cutis laxa, autosomal recessive, type IIIAMIM #219150

Spastic paraplegia 9A, autosomal dominantMIM #601162

Spastic paraplegia 9B, autosomal recessiveMIM #616586

Clinical highlights

Gene-disease validity (ClinGen)

P5CS deficiency · SDDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

Curated mechanisms (Gene2Phenotype) include both loss of function and gain of function. Which applies is variant-dependent — do not assume a null variant is, or isn’t, the pathogenic class without checking the specific variant.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

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LOEUF

Multiple*

Mechanism· G2P

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