ALDH18A1

Chr 10ADAR

aldehyde dehydrogenase 18 family member A1

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

NCBI Gene: 5832ENSG00000059573UniProt: P54886

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]

Primary Disease Associations & Inheritance

Cutis laxa, autosomal dominant 3MIM #616603
AD
Cutis laxa, autosomal recessive, type IIIAMIM #219150
AR
Spastic paraplegia 9A, autosomal dominantMIM #601162
AD
Spastic paraplegia 9B, autosomal recessiveMIM #616586
AR
0
ClinVar variants
0
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ALDH18A1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.
Some data sources returned errors (1)

clinvarCount: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.97Z-score
OE missense 0.74 (0.67–0.81)
325 obs / 441.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.33 (0.21–0.52)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.74 (0.67–0.81)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95
0≤1.21.6
LoF obs/exp: 13 / 39.8Missense obs/exp: 325 / 441.2Syn Z: 0.48

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

ALDH18A1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ALDH18A1-related spastic paraplegia (biallelic)

limited
ARUndeterminedAltered Gene Product Structure
Eye
G2P ↗
missense variantinframe deletioninframe insertion

ALDH18A1-related cutis laxa

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. DisordersEye
G2P ↗

ALDH18A1-related spastic paraplegia (monoallelic)

definitive
ADDominant NegativeAltered Gene Product Structure
Dev. DisordersEye
G2P ↗

ALDH18A1-related developmental disorder-joint hypermobility-skin laxity with or without metabolic abnormalities

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cutis laxa, autosomal dominant 3

MIM #616603

Molecular basis of disorder known

Autosomal dominant

Cutis laxa, autosomal recessive, type IIIA

MIM #219150

Molecular basis of disorder known

Autosomal recessive

Spastic paraplegia 9A, autosomal dominant

MIM #601162

Molecular basis of disorder known

Autosomal dominant

Spastic paraplegia 9B, autosomal recessive

MIM #616586

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Inhibition of the proline metabolism rate-limiting enzyme P5CS allows proliferation of glutamine-restricted cancer cells.
Linder SJ et al.·Nat Metab
2023
ALDH Enzymes and Hematological Diseases: A Scoping Review of Literature.
Foucault A et al.·Discov Med
2024Review
Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature.
Wolthuis DF et al.·Eur J Paediatr Neurol
2014Review
A novel case of autosomal-dominant cutis laxa caused by a de novo likely pathogenic variant in ALDH18A1: case report and literature review.
Ahmad F et al.·J Hum Genet
2025Review
Atlantoaxial instability associated with ALDH18A1 mutation.
Lucas AT et al.·Am J Med Genet A
2023Case report
Δ(1) -Pyrroline-5-carboxylate synthetase deficiency: An emergent multifaceted urea cycle-related disorder.
Marco-Marín C et al.·J Inherit Metab Dis
2020Review
Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates MYCN-amplified neuroblastoma growth.
Guo YF et al.·Sci Transl Med
2020
Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism.
Colonna MB et al.·Hum Mol Genet
2023Functional
[Autosomal dominant spastic paraplegias].
Rudenskaya GE et al.·Zh Nevrol Psikhiatr Im S S Korsakova
2021
Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families.
Zaman Q et al.·J Gene Med
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools