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)

Definitive · P5CS deficiency · SD · ClinGen 2021

Interpreting a novel variant

The dominant disease is caused by gain-of-function changes and the recessive disease by loss of function (Gene2Phenotype). A single heterozygous truncating variant therefore fits the recessive disease and does not by itself explain a dominant presentation; a novel missense has to be read against the dominant mechanism.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.52

LOEUF

Multiple*

Mechanism· G2P

📖

GeneReview available — ALDH18A1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in ALDH18A1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 92

839 rare PASS variants

Rare truncating (LoF)

1 in 2,700

96 rare PASS variants

Rare synonymous (reference)

1 in 130

354 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ALDH18A1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	1 in 2,900
South Asian	~43k	1 in 71	1 in 2,900
Remaining (unassigned)	~30k	1 in 72	1 in 3,000
European (Finnish)	~27k	1 in 240	≈ 1 in 8,900
Admixed American	~22k	1 in 95	≈ 1 in 10,000
African / African American	~21k	1 in 74	1 in 2,000
East Asian	~20k	1 in 80	≈ 1 in 4,000
Ashkenazi Jewish	~13k	1 in 430	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 100	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 17 of 17 coding exons well covered in gnomAD exomes. Genomes: 16 of 17 (exon 2 below).? see exons ↓