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GeneE
25 sources retrieved Β· Most recent: April 2026 Β· Index updated 15 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
ALDH18A1
aldehyde dehydrogenase 18 family member A1
Chromosome 10 Β· 10q24.1
NCBI Gene: 5832Ensembl: ENSG00000059573.10HGNC: HGNC:9722UniProt: P54886
182PubMed Papers
24Diseases
0Drugs
59Pathogenic Variants
FUNCTIONAL ROLE
Hub GeneKinase
RESEARCH IMPACT
TrendingVariant-Rich
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
RNA bindingglutamate 5-kinase activityglutamate-5-semialdehyde dehydrogenase activityprotein bindingALDH18A1-related de Barsy syndromecutis laxa, autosomal dominant 3autosomal recessive complex spastic paraplegia type 9Bautosomal dominant spastic paraplegia type 9
✦AI Summary

ALDH18A1 encodes P5CS (pyrroline-5-carboxylate synthase), a bifunctional enzyme that catalyzes the rate-limiting step in proline biosynthesis by converting glutamate to glutamate 5-semialdehyde 1. This enzyme plays a crucial role in amino acid metabolism, particularly in the glutamine-arginine-proline metabolic axis 2. P5CS functions as a major consumer of glutamate and enables cancer cells to adapt to nutrient stress by promoting de novo glutamine synthesis when proline biosynthesis is reduced 1. The enzyme has been identified as a metabolic target in cancer, with expression regulated by histone acetylation in hepatocellular carcinoma 3 and serving as a potential angiogenic target 4. ALDH18A1 mutations cause multiple genetic disorders including autosomal recessive cutis laxa type 3A and hereditary spastic paraplegia (SPG9A/9B) 56. Patients with ALDH18A1 mutations present with diverse clinical features including cutis laxa, joint laxity, developmental delays, microcephaly, and neurological involvement 6. The enzyme's role in metabolic reprogramming makes it an attractive therapeutic target for cancer treatment 27.

Sources cited
1
ALDH18A1 encodes P5CS, the rate-limiting enzyme in proline biosynthesis, and its downregulation promotes de novo glutamine synthesis
PMID: 37957387
2
P5CS is a key enzyme in the glutamine-arginine-proline metabolic axis and represents a therapeutic target in cancer
PMID: 39051546
3
ALDH18A1 expression is regulated by histone acetylation in hepatocellular carcinoma
PMID: 33361394
4
ALDH18A1 was identified as a previously unknown metabolic angiogenic target
PMID: 32268117
5
Novel mutations in ALDH18A1 cause spastic paraplegia disease
PMID: 36239107
6
ALDH18A1 mutations cause autosomal recessive cutis laxa with diverse clinical features including cutis laxa, developmental delays, and neurological involvement
PMID: 24767728
7
ALDH18A1 and PYCR enzymes upregulation promotes cancer cell proliferation and invasion
PMID: 34390414
Disease Associationsβ“˜24
ALDH18A1-related de Barsy syndromeOpen Targets
0.83Strong
cutis laxa, autosomal dominant 3Open Targets
0.82Strong
autosomal recessive complex spastic paraplegia type 9BOpen Targets
0.81Strong
autosomal dominant spastic paraplegia type 9Open Targets
0.71Strong
de Barsy syndromeOpen Targets
0.66Moderate
genetic disorderOpen Targets
0.49Moderate
P5CS deficiencyOpen Targets
0.45Moderate
cutis laxaOpen Targets
0.38Weak
autosomal dominant cutis laxaOpen Targets
0.37Weak
Intellectual disabilityOpen Targets
0.35Weak
hereditary spastic paraplegiaOpen Targets
0.34Weak
neuroendocrine neoplasmOpen Targets
0.28Weak
hereditary spastic paraplegia 5AOpen Targets
0.27Weak
Abnormality of the nervous systemOpen Targets
0.27Weak
spondyloepiphyseal dysplasia, Stanescu typeOpen Targets
0.15Weak
diverticular diseaseOpen Targets
0.14Weak
Hearing impairmentOpen Targets
0.12Weak
hereditary ataxiaOpen Targets
0.12Weak
hepatocellular carcinomaOpen Targets
0.10Weak
bladder transitional cell carcinomaOpen Targets
0.08Suggestive
Cutis laxa, autosomal dominant, 3UniProt
Cutis laxa, autosomal recessive, 3AUniProt
Spastic paraplegia 9A, autosomal dominantUniProt
Spastic paraplegia 9B, autosomal recessiveUniProt
Pathogenic Variants59
NM_002860.4(ALDH18A1):c.809-1G>ALikely pathogenic
not provided|Cutis laxa, autosomal dominant 3;Autosomal dominant spastic paraplegia type 9;de Barsy syndrome
β˜…β˜…β˜†β˜†2026
NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)Pathogenic
Hereditary spastic paraplegia 9A|not provided|ALDH18A1 deficiency|Cutis laxa, autosomal dominant 3;Autosomal dominant spastic paraplegia type 9;de Barsy syndrome|P5CS deficiency
β˜…β˜…β˜†β˜†2026β†’ Residue 252
NM_002860.4(ALDH18A1):c.2143G>C (p.Asp715His)Likely pathogenic
Autosomal recessive complex spastic paraplegia type 9B|Cutis laxa, autosomal dominant 3|de Barsy syndrome;Cutis laxa, autosomal dominant 3;Autosomal dominant spastic paraplegia type 9
β˜…β˜…β˜†β˜†2026β†’ Residue 715
NM_002860.4(ALDH18A1):c.475C>T (p.Arg159Ter)Pathogenic
not provided|Autosomal dominant spastic paraplegia type 9;Cutis laxa, autosomal dominant 3;de Barsy syndrome|Hereditary spastic paraplegia 9A
β˜…β˜…β˜†β˜†2025β†’ Residue 159
NM_002860.4(ALDH18A1):c.1321C>T (p.Arg441Ter)Pathogenic
Cutis laxa, autosomal dominant 3;de Barsy syndrome;Autosomal dominant spastic paraplegia type 9|Autosomal recessive complex spastic paraplegia type 9B
β˜…β˜…β˜†β˜†2025β†’ Residue 441
NM_002860.4(ALDH18A1):c.1111C>T (p.Arg371Ter)Pathogenic
Hereditary spastic paraplegia|Autosomal recessive complex spastic paraplegia type 9B
β˜…β˜…β˜†β˜†2025β†’ Residue 371
NM_002860.4(ALDH18A1):c.88+1G>ALikely pathogenic
ALDH18A1-related de Barsy syndrome|ALDH18A1-related disorder|not provided|Cutis laxa, autosomal dominant 3;Autosomal dominant spastic paraplegia type 9;de Barsy syndrome
β˜…β˜…β˜†β˜†2025
NM_002860.4(ALDH18A1):c.1596_1600del (p.Val533fs)Pathogenic
Autosomal recessive complex spastic paraplegia type 9B|Autosomal dominant spastic paraplegia type 9;de Barsy syndrome;Cutis laxa, autosomal dominant 3
β˜…β˜…β˜†β˜†2025β†’ Residue 533
NM_002860.4(ALDH18A1):c.1993C>T (p.Arg665Ter)Pathogenic
ALDH18A1-related disorder|Autosomal dominant spastic paraplegia type 9;Cutis laxa, autosomal dominant 3;de Barsy syndrome
β˜…β˜…β˜†β˜†2025β†’ Residue 665
NM_002860.4(ALDH18A1):c.250C>T (p.Arg84Ter)Pathogenic
Inborn genetic diseases|Autosomal dominant spastic paraplegia type 9;Cutis laxa, autosomal dominant 3;de Barsy syndrome|Autosomal recessive complex spastic paraplegia type 9B
β˜…β˜…β˜†β˜†2025β†’ Residue 84
NM_002860.4(ALDH18A1):c.2246G>A (p.Arg749Gln)Pathogenic
not provided|ALDH18A1-related de Barsy syndrome|de Barsy syndrome;Autosomal dominant spastic paraplegia type 9;Cutis laxa, autosomal dominant 3
β˜…β˜…β˜†β˜†2024β†’ Residue 749
NM_002860.4(ALDH18A1):c.413G>A (p.Arg138Gln)Pathogenic
Cutis laxa, autosomal dominant 3|not provided|Autosomal dominant spastic paraplegia type 9;Cutis laxa, autosomal dominant 3;de Barsy syndrome|ALDH18A1-related disorder|Hereditary spastic paraplegia 9A
β˜…β˜…β˜†β˜†2024β†’ Residue 138
NM_002860.4(ALDH18A1):c.1375C>T (p.Arg459Ter)Pathogenic
not provided
β˜…β˜…β˜†β˜†2024β†’ Residue 459
NM_002860.4(ALDH18A1):c.377G>A (p.Arg126His)Likely pathogenic
Cutis laxa, autosomal dominant 3|Autosomal recessive complex spastic paraplegia type 9B;Cutis laxa, autosomal dominant 3;Hereditary spastic paraplegia 9A;ALDH18A1-related de Barsy syndrome
β˜…β˜…β˜†β˜†2023β†’ Residue 126
NM_002860.4(ALDH18A1):c.754C>T (p.Arg252Ter)Pathogenic
not provided|Autosomal dominant spastic paraplegia type 9;de Barsy syndrome;Cutis laxa, autosomal dominant 3
β˜…β˜…β˜†β˜†2023β†’ Residue 252
NM_002860.4(ALDH18A1):c.301C>T (p.Gln101Ter)Pathogenic
not provided|Inborn genetic diseases
β˜…β˜…β˜†β˜†2023β†’ Residue 101
NM_002860.4(ALDH18A1):c.412C>T (p.Arg138Trp)Pathogenic
Cutis laxa, autosomal dominant 3|not provided|Cutis laxa, autosomal dominant 3;Hereditary spastic paraplegia 9A;ALDH18A1-related de Barsy syndrome;Autosomal recessive complex spastic paraplegia type 9B
β˜…β˜…β˜†β˜†2022β†’ Residue 138
NM_002860.4(ALDH18A1):c.1274G>A (p.Arg425His)Likely pathogenic
Cutis laxa, autosomal dominant 3;Autosomal dominant spastic paraplegia type 9;de Barsy syndrome
β˜…β˜†β˜†β˜†2026β†’ Residue 425
NM_002860.4(ALDH18A1):c.191G>A (p.Arg64His)Likely pathogenic
Cutis laxa, autosomal dominant 3;Autosomal dominant spastic paraplegia type 9;de Barsy syndrome
β˜…β˜†β˜†β˜†2025β†’ Residue 64
NM_002860.4(ALDH18A1):c.2110+1G>TLikely pathogenic
Cutis laxa, autosomal dominant 3;Autosomal dominant spastic paraplegia type 9;de Barsy syndrome
β˜…β˜†β˜†β˜†2025
View on ClinVar β†—
Related Genes
MTHFD2Protein interaction98%SHMT2Protein interaction97%ALDH4A1Protein interaction97%ZFYVE27Protein interaction96%PHGDHProtein interaction93%PRODHProtein interaction92%
Tissue Expression6 tissues
Bone Marrow
100%
Liver
87%
Ovary
53%
Brain
52%
Heart
45%
Lung
38%
Gene Interaction Network
Click a node to explore
ALDH18A1MTHFD2SHMT2ALDH4A1ZFYVE27PHGDHPRODH
PROTEIN STRUCTURE
Preparing viewer…
PDB2H5G Β· 2.25 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.62LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.48 [0.38–0.62]
RankingsWhere ALDH18A1 stands among ~20K protein-coding genes
  • #2,374of 20,598
    Most Researched182 Β· top quartile
  • #1,184of 5,498
    Most Pathogenic Variants59 Β· top quartile
  • #4,305of 17,882
    Most Constrained (LOEUF)0.62 Β· top quartile
Genes detectedALDH18A1
Sources retrieved25 papers
Response timeβ€”
πŸ“„ Sources
25β–Ό
1
Single-Cell RNA Sequencing Maps Endothelial Metabolic Plasticity in Pathological Angiogenesis.
PMID: 32268117
Cell Metab Β· 2020
1.00
2
Targeting the glutamine-arginine-proline metabolism axis in cancer.
PMID: 39051546
J Enzyme Inhib Med Chem Β· 2024
0.90
3
Targeting p300/CBP Attenuates Hepatocellular Carcinoma Progression through Epigenetic Regulation of Metabolism.
PMID: 33361394
Cancer Res Β· 2021
0.80
4
Inhibition of the proline metabolism rate-limiting enzyme P5CS allows proliferation of glutamine-restricted cancer cells.
PMID: 37957387
Nat Metab Β· 2023
0.70
5
Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates
PMID: 32075946
Sci Transl Med Β· 2020
0.68