ALDH18A1

Summary

ALDH18A1 (aldehyde dehydrogenase 18 family member A1, HGNC:9722) is a protein-coding gene on chromosome 10q24.1, encoding Delta-1-pyrroline-5-carboxylate synthase (P54886). Bifunctional enzyme that converts glutamate to glutamate 5-semialdehyde, an intermediate in the biosynthesis of proline, ornithine and arginine.

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.

Source: NCBI Gene 5832 — RefSeq curated summary.

At a glance

• Gene–disease (curated): P5CS deficiency (Definitive, ClinGen) — +7 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 897 total — 33 pathogenic, 22 likely-pathogenic
• Phenotypes (HPO): 184
• Druggable target: yes
• MANE Select transcript: NM_002860

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9722
Approved symbol	ALDH18A1
Name	aldehyde dehydrogenase 18 family member A1
Location	10q24.1
Locus type	gene with protein product
Status	Approved
Aliases	P5CS
Ensembl gene	ENSG00000059573
Ensembl biotype	protein_coding
OMIM	138250
Entrez	5832

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 20 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000371221, ENST00000371224, ENST00000483788, ENST00000485428, ENST00000489386, ENST00000879374, ENST00000879375, ENST00000879376, ENST00000879377, ENST00000879378, ENST00000879379, ENST00000879380, ENST00000879381, ENST00000879382, ENST00000931927, ENST00000931928, ENST00000931929, ENST00000931930, ENST00000931931, ENST00000931932, ENST00000931933, ENST00000931934, ENST00000963326

RefSeq mRNA: 10 — MANE Select: NM_002860 NM_001017423, NM_001323412, NM_001323413, NM_001323414, NM_001323415, NM_001323416, NM_001323417, NM_001323418, NM_001323419, NM_002860

CCDS: CCDS31257, CCDS7443

Canonical transcript exons

ENST00000371224 — 18 exons

Exon	Start	End
ENSE00000716950	95625362	95625455
ENSE00000716959	95633491	95633649
ENSE00000987352	95632959	95633049
ENSE00000987353	95621031	95621251
ENSE00000987354	95616477	95616614
ENSE00000987358	95610197	95610292
ENSE00001843244	95605941	95606943
ENSE00003500410	95653290	95653405
ENSE00003514350	95637287	95637436
ENSE00003533076	95613742	95613863
ENSE00003594952	95637093	95637197
ENSE00003602703	95642992	95643206
ENSE00003606814	95627442	95627586
ENSE00003626158	95628368	95628492
ENSE00003626836	95626703	95626776
ENSE00003629956	95613966	95614161
ENSE00003691060	95611256	95611442
ENSE00003850871	95656597	95656711

Expression profiles

Bgee: expression breadth ubiquitous, 263 present calls, max score 98.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.1685 / max 160.0143, expressed in 1760 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110818	22.8983	1756
110820	1.2271	693
110819	0.7900	479
110821	0.2531	106

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	98.63	gold quality
jejunal mucosa	UBERON:0000399	98.14	gold quality
ileal mucosa	UBERON:0000331	97.98	gold quality
tibia	UBERON:0000979	97.69	gold quality
duodenum	UBERON:0002114	97.22	gold quality
colonic mucosa	UBERON:0000317	96.30	gold quality
rectum	UBERON:0001052	96.30	gold quality
mucosa of transverse colon	UBERON:0004991	96.05	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.59	gold quality
secondary oocyte	CL:0000655	95.44	gold quality
body of pancreas	UBERON:0001150	95.44	gold quality
stromal cell of endometrium	CL:0002255	95.34	gold quality
islet of Langerhans	UBERON:0000006	95.23	gold quality
pancreas	UBERON:0001264	94.74	gold quality
cartilage tissue	UBERON:0002418	93.89	gold quality
saliva-secreting gland	UBERON:0001044	93.70	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.53	gold quality
small intestine	UBERON:0002108	93.49	gold quality
ventricular zone	UBERON:0003053	93.29	gold quality
embryo	UBERON:0000922	93.18	gold quality
ganglionic eminence	UBERON:0004023	93.04	gold quality
transverse colon	UBERON:0001157	92.87	gold quality
minor salivary gland	UBERON:0001830	92.51	gold quality
seminal vesicle	UBERON:0000998	92.47	gold quality
right lobe of thyroid gland	UBERON:0001119	92.03	gold quality
mouth mucosa	UBERON:0003729	92.01	gold quality
oocyte	CL:0000023	91.81	gold quality
tonsil	UBERON:0002372	91.49	gold quality
gall bladder	UBERON:0002110	91.45	gold quality
pituitary gland	UBERON:0000007	91.41	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.46
E-MTAB-7303	no	125.70

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1

miRNA regulators (miRDB)

35 targeting ALDH18A1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-4502	99.65	66.99	1021
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-8066	99.05	68.66	1532
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-3164	99.02	68.39	1071
HSA-MIR-6820-3P	99.02	68.50	1035
HSA-MIR-3124-3P	98.87	68.95	2123
HSA-MIR-6827-5P	98.46	64.88	1256
HSA-MIR-4443	98.02	66.25	1928

Literature-anchored findings (GeneRIF, showing 15)

• analysis of function and regulation of Delta1-pyrroline-5-carboxylate synthase (PMID:18401542)
• These data suggest that P5CS may possess additional uncharacterised functions that affect connective tissue and central nervous system function. (PMID:18478038)
• ALDH18A1 genetic variants are associated with Down syndrome in subjects with dementia of Alzheimer’s disease. (PMID:20946940)
• expansion of the phenotypic spectrum associated with mutations in ALDH18A1 (PMID:21739576)
• A frameshift deletion of one nucleotide and a microdeletion affecting the ALDH18A1 gene, respectively, in a homozygous state in both patients, was identified. (PMID:24913064)
• autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic paraplegia with marked cognitive impairment (PMID:26026163)
• Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa. (PMID:26320891)
• ALDH18A1 gene during vertebrate and invertebrate evolution and a proposal for generating the bifunctional vertebrate and invertebrate ALDH18A1 gene from a bacterial operon (proBA) encoding glutamyl kinase and glutamyl phosphate reductase. (PMID:27989597)
• This is the first report of an individual with ALDH18A1-ADCL due to a substitution at a residue other than p.Arg138. Knowledge of the complete spectrum of dominant-acting mutations that cause this rare syndrome will have implications for molecular diagnosis and genetic counselling of these families. (PMID:28228640)
• Novel mutations in the ALDH18A1 gene in complicated hereditary spastic paraplegia with cerebellar ataxia and cognitive impairment. (PMID:29915212)
• Delta(1) -Pyrroline-5-carboxylate synthetase deficiency: An emergent multifaceted urea cycle-related disorder. (PMID:32017139)
• Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates MYCN-amplified neuroblastoma growth. (PMID:32075946)
• SPG9A with the new occurrence of an ALDH18A1 mutation in a CMT1A family with PMP22 duplication: case report. (PMID:33573605)
• Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism. (PMID:36067040)
• Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families. (PMID:37119015)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Aldh18a1	ENSMUSG00000025007
rattus_norvegicus	Aldh18a1	ENSRNOG00000067262
drosophila_melanogaster	P5CS	FBGN0037146
caenorhabditis_elegans		WBGENE00011938

Protein

Protein identifiers

Delta-1-pyrroline-5-carboxylate synthase — P54886 (reviewed: P54886)

Alternative names: Aldehyde dehydrogenase family 18 member A1

All UniProt accessions (1): P54886

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional enzyme that converts glutamate to glutamate 5-semialdehyde, an intermediate in the biosynthesis of proline, ornithine and arginine.

Subunit / interactions. Can form homodimers/multimers.

Subcellular location. Mitochondrion. Mitochondrion matrix.

Disease relevance. Cutis laxa, autosomal recessive, 3A (ARCL3A) [MIM:219150] A syndrome characterized by facial dysmorphism with a progeroid appearance, large and late-closing fontanel, cutis laxa, joint hyperlaxity, athetoid movements and hyperreflexia, pre- and postnatal growth retardation, intellectual deficit, developmental delay, and ophthalmologic abnormalities. The disease is caused by variants affecting the gene represented in this entry. Cutis laxa, autosomal dominant, 3 (ADCL3) [MIM:616603] A form of cutis laxa, a connective tissue disorder characterized by loose, hyperextensible skin with decreased resilience and elasticity leading to a premature aged appearance. Face, hands, feet, joints, and torso may be differentially affected. Additional variable clinical features are gastrointestinal diverticula, hernia, and genital prolapse. Rare manifestations are pulmonary artery stenosis, aortic aneurysm, bronchiectasis, and emphysema. ADCL3 patients manifest thin skin with visible veins and wrinkles, cataract or corneal clouding, moderate intellectual disability, muscular hypotonia with brisk muscle reflexes, clenched fingers, and pre- and postnatal growth retardation. The disease is caused by variants affecting the gene represented in this entry. Spastic paraplegia 9A, autosomal dominant (SPG9A) [MIM:601162] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG9A patients have gait difficulties, motor neuropathy, and dysarthria. Additional variable features include cerebellar signs, cataract, pes cavus, and urinary urgency. The disease is caused by variants affecting the gene represented in this entry. Spastic paraplegia 9B, autosomal recessive (SPG9B) [MIM:616586] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG9B is a complex form characterized by delayed psychomotor development, intellectual disability, and severe motor impairment. Dysmorphic facial features, tremor, and urinary incontinence are variably observed in SPG9B patients. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Isoform Short: Inhibited by L-ornithine with a Ki of approximately 0.25 mm. Isoform Long: Insensitive to ornithine inhibition. This is due to the two amino acid insert which abolishes feedback inhibition of P5CS activity by L-ornithine.

Pathway. Amino-acid biosynthesis; L-proline biosynthesis; L-glutamate 5-semialdehyde from L-glutamate: step 1/2. Amino-acid biosynthesis; L-proline biosynthesis; L-glutamate 5-semialdehyde from L-glutamate: step 2/2.

Similarity. In the N-terminal section; belongs to the glutamate 5-kinase family. In the C-terminal section; belongs to the gamma-glutamyl phosphate reductase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P54886-1	Long	yes
P54886-2	Short

RefSeq proteins (10): NP_001017423, NP_001310341, NP_001310342, NP_001310343, NP_001310344, NP_001310345, NP_001310346, NP_001310347, NP_001310348, NP_002851* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000965	GPR_dom	Domain
IPR001048	Asp/Glu/Uridylate_kinase	Domain
IPR001057	Glu/AcGlu_kinase	Family
IPR005715	Glu_5kinase/COase_Synthase	Family
IPR005766	P5_carboxy_syn	Family
IPR015590	Aldehyde_DH_dom	Domain
IPR016161	Ald_DH/histidinol_DH	Homologous_superfamily
IPR016162	Ald_DH_N	Homologous_superfamily
IPR016163	Ald_DH_C	Homologous_superfamily
IPR019797	Glutamate_5-kinase_CS	Conserved_site
IPR020593	G-glutamylP_reductase_CS	Conserved_site
IPR036393	AceGlu_kinase-like_sf	Homologous_superfamily
IPR041744	G5K_ProBA	Domain

Pfam: PF00171, PF00696

Catalyzed reactions (Rhea), 2 shown:

• L-glutamate + ATP = L-glutamyl 5-phosphate + ADP (RHEA:14877)
• L-glutamate 5-semialdehyde + phosphate + NADP(+) = L-glutamyl 5-phosphate + NADPH + H(+) (RHEA:19541)

UniProt features (78 total): helix 19, sequence variant 17, strand 15, sequence conflict 7, binding site 5, mutagenesis site 4, turn 4, modified residue 3, region of interest 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2H5G	X-RAY DIFFRACTION	2.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54886-F1	84.05	0.60

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (5): 117; 223; 246; 266–267; 305–311

Post-translational modifications (3): 550, 311, 347

Mutagenesis-validated functional residues (4):

Position	Phenotype
76	no effect on punctate pattern in the mitochondria; when associated with a-247 and a-311.
247	no effect on punctate pattern in the mitochondria; when associated with a-76 and a-311.
311	no effect on punctate pattern in the mitochondria; when associated with a-247 and a-247.
612	catalytically inactive; no effect on filament formation; no effect on punctate pattern in the mitochondria.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-8964539	Glutamate and glutamine metabolism

MSigDB gene sets: 585 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_GLUTAMATE_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, PATIL_LIVER_CANCER, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, ROZANOV_MMP14_TARGETS_UP, MARTIN_VIRAL_GPCR_SIGNALING_DN, GOCC_MITOCHONDRIAL_ENVELOPE

GO Biological Process (7): glutamate metabolic process (GO:0006536), L-ornithine biosynthetic process (GO:0006592), response to temperature stimulus (GO:0009266), L-citrulline biosynthetic process (GO:0019240), L-proline biosynthetic process (GO:0055129), obsolete proline biosynthetic process (GO:0006561), amino acid biosynthetic process (GO:0008652)

GO Molecular Function (12): RNA binding (GO:0003723), glutamate 5-kinase activity (GO:0004349), glutamate-5-semialdehyde dehydrogenase activity (GO:0004350), ATP binding (GO:0005524), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), kinase activity (GO:0016301), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor (GO:0016620), transferase activity (GO:0016740)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), cytoplasm (GO:0005737), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of proteins	1
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
amino acid metabolic process	2
amino acid biosynthetic process	2
non-proteinogenic amino acid biosynthetic process	2
catalytic activity	2
mitochondrion	2
dicarboxylic acid metabolic process	1
ornithine metabolic process	1
response to abiotic stimulus	1
L-proline metabolic process	1
glutamate family amino acid biosynthetic process	1
biosynthetic process	1
nucleic acid binding	1
phosphotransferase activity, carboxyl group as acceptor	1
amino acid kinase activity	1
oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
oxidoreductase activity, acting on the aldehyde or oxo group of donors	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
intracellular organelle lumen	1
intracellular anatomical structure	1
cellular anatomical structure	1
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

6954 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALDH18A1	PYCR1	P32322	956
ALDH18A1	ALDH4A1	P30038	899
ALDH18A1	PRODH	O43272	861
ALDH18A1	PRODH	O43272	859
ALDH18A1	OAT	P04181	811
ALDH18A1	ZFYVE27	Q5T4F4	810
ALDH18A1	PYCR2	Q96C36	776
ALDH18A1	PYCR3	Q53H96	775
ALDH18A1	OPN5	Q6U736	775
ALDH18A1	HTR5A	P47898	762
ALDH18A1	SPAST	Q9UBP0	762
ALDH18A1	FFAR3	O14843	760
ALDH18A1	FFAR2	O15552	755
ALDH18A1	OXGR1	Q96P68	735
ALDH18A1	WASHC5	Q12768	733

IntAct

135 interactions, top by confidence:

A	B	Type	Score
EDC3	DDX6	psi-mi:“MI:0914”(association)	0.960
EMC3	EMC8	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ALDH18A1	AGTRAP	psi-mi:“MI:0915”(physical association)	0.560
CMTM5	ALDH18A1	psi-mi:“MI:0915”(physical association)	0.560
AGTRAP	ALDH18A1	psi-mi:“MI:0915”(physical association)	0.560
ALDH18A1	CMTM5	psi-mi:“MI:0915”(physical association)	0.560
ALDH18A1	DARS2	psi-mi:“MI:0915”(physical association)	0.560
	ALDH18A1	psi-mi:“MI:0915”(physical association)	0.560
COQ9	ALDH18A1	psi-mi:“MI:0915”(physical association)	0.560
ALDH18A1	rep	psi-mi:“MI:0915”(physical association)	0.550
CLTB	PIK3C2A	psi-mi:“MI:0914”(association)	0.530
RALB	DBT	psi-mi:“MI:0914”(association)	0.530
rep	NKRF	psi-mi:“MI:0914”(association)	0.500
Lats2	MPDZ	psi-mi:“MI:0914”(association)	0.420
Mical3	SSB	psi-mi:“MI:0915”(physical association)	0.400
Cbx1	FLOT1	psi-mi:“MI:0915”(physical association)	0.400
Trim69		psi-mi:“MI:0915”(physical association)	0.400
Haus1	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
LLGL2	RBBP6	psi-mi:“MI:0914”(association)	0.350
DCP1A	TBX3	psi-mi:“MI:0914”(association)	0.350
TUBGCP5	DNAJC6	psi-mi:“MI:0914”(association)	0.350
C1qbp		psi-mi:“MI:0914”(association)	0.350
CERK	WDR46	psi-mi:“MI:0914”(association)	0.350

BioGRID (262): AGTRAP (Two-hybrid), CMTM5 (Two-hybrid), ALDH18A1 (Affinity Capture-RNA), ALDH18A1 (Affinity Capture-RNA), ALDH18A1 (Affinity Capture-RNA), ALDH18A1 (Affinity Capture-MS), ALDH18A1 (Affinity Capture-MS), ALDH18A1 (Affinity Capture-MS), ALDH18A1 (Affinity Capture-MS), ALDH18A1 (Affinity Capture-MS), ALDH18A1 (Affinity Capture-MS), ALDH18A1 (Affinity Capture-MS), ALDH18A1 (Affinity Capture-MS), ALDH18A1 (Affinity Capture-MS), ALDH18A1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0D2YG09, A0A1D8PMB8, A0A2G5IC53, A0A4P8DJE6, A0FKE6, C4QXA5, C9K7B8, J9VS37, K3VH30, O42615, O42938, O60163, O74468, O94200, O94634, P00927, P0DTA4, P10869, P14882, P16638, P16861, P16862, P25306, P34229, P49079, P53396, P53585, P54886, P54889, P78820, P78875, Q03216, Q0CS62, Q2I0M6, Q2TCH3, Q32PF2, Q42777, Q5I0C3, Q5R4M8, Q8NJU8

Diamond homologs: A0PXA4, A1AUT0, A1U3C3, A2BQ71, A2BVQ3, A2C148, A2CAS7, A3DC22, A3PBW4, A4G8E9, A4J3Q0, A4VR07, A4W6X5, A4XK60, A5CZ28, A5G906, A5GJS5, A5GSH0, A5IKB6, A6LPD5, A6Q3B4, A6V0A3, A6VZ85, A8G3V6, A8MFQ5, A9BJ18, A9MNR4, B0CFL0, B0JWW5, B0K0T2, B0K9C5, B0TBV8, B1L9J9, B1XLA4, B2IZ89, B2THG5, B2UX78, B3E3M7, B5YK66, B7V8A7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

897 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	22
Uncertain significance	460
Likely benign	233
Benign	63

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
156546	NM_002860.4(ALDH18A1):c.2131del (p.Leu711fs)	Pathogenic
16086	NM_002860.4(ALDH18A1):c.2350C>T (p.His784Tyr)	Pathogenic
1685516	NM_002860.4(ALDH18A1):c.401C>T (p.Ser134Phe)	Pathogenic
2003911	NM_002860.4(ALDH18A1):c.545del (p.Ile182fs)	Pathogenic
2035292	NM_002860.4(ALDH18A1):c.2117_2118del (p.Thr706fs)	Pathogenic
217117	NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)	Pathogenic
217118	NM_002860.4(ALDH18A1):c.359T>C (p.Val120Ala)	Pathogenic
217119	NM_002860.4(ALDH18A1):c.1994G>T (p.Arg665Leu)	Pathogenic
217120	NM_002860.4(ALDH18A1):c.1910T>C (p.Leu637Pro)	Pathogenic
217259	NM_002860.4(ALDH18A1):c.412C>T (p.Arg138Trp)	Pathogenic
217260	NM_002860.4(ALDH18A1):c.413G>A (p.Arg138Gln)	Pathogenic
217261	NM_002860.4(ALDH18A1):c.413G>T (p.Arg138Leu)	Pathogenic
2253522	NM_002860.4(ALDH18A1):c.250C>T (p.Arg84Ter)	Pathogenic
2424550	NC_000010.10:g.(?97376214)(97376391_?)del	Pathogenic
2446762	GRCh37/hg19 10q23.32-24.1(chr10:93281410-97596360)x1	Pathogenic
2924294	NM_002860.4(ALDH18A1):c.1321C>T (p.Arg441Ter)	Pathogenic
2930570	NM_002860.4(ALDH18A1):c.1795del (p.Arg599fs)	Pathogenic
2939892	NM_002860.4(ALDH18A1):c.1227dup (p.Asp410fs)	Pathogenic
2940959	NM_002860.4(ALDH18A1):c.339del (p.Met113fs)	Pathogenic
2949341	NM_002860.4(ALDH18A1):c.1804del (p.Arg602fs)	Pathogenic
2950800	NM_002860.4(ALDH18A1):c.1713dup (p.Lys572Ter)	Pathogenic
29727	NM_002860.4(ALDH18A1):c.1923+1G>A	Pathogenic
3244833	NC_000010.10:g.(?97366519)(97626140_?)del	Pathogenic
3283380	NM_002860.4(ALDH18A1):c.1804A>T (p.Arg602Ter)	Pathogenic
3756046	NM_002860.4(ALDH18A1):c.467T>G (p.Leu156Ter)	Pathogenic
3760154	NM_002860.4(ALDH18A1):c.684dup (p.Ala229fs)	Pathogenic
3767627	NM_002860.4(ALDH18A1):c.475C>T (p.Arg159Ter)	Pathogenic
392664	NM_002860.4(ALDH18A1):c.754C>T (p.Arg252Ter)	Pathogenic
459841	NM_002860.4(ALDH18A1):c.741del (p.Asp247fs)	Pathogenic
4794356	NM_002860.4(ALDH18A1):c.1702C>T (p.Gln568Ter)	Pathogenic

SpliceAI

2650 predictions. Top by Δscore:

Variant	Effect	Δscore
10:95610191:TCTTA:T	donor_loss	1.0000
10:95610192:CTTAC:C	donor_loss	1.0000
10:95610193:TTA:T	donor_loss	1.0000
10:95610194:TACC:T	donor_loss	1.0000
10:95610195:A:C	donor_loss	1.0000
10:95610195:AC:A	donor_gain	1.0000
10:95610196:C:CG	donor_loss	1.0000
10:95610196:CC:C	donor_gain	1.0000
10:95610288:GTTTT:G	acceptor_gain	1.0000
10:95610289:TTTT:T	acceptor_gain	1.0000
10:95610290:TTT:T	acceptor_gain	1.0000
10:95610291:TT:T	acceptor_gain	1.0000
10:95610292:TC:T	acceptor_loss	1.0000
10:95610293:C:CA	acceptor_loss	1.0000
10:95610293:C:CC	acceptor_gain	1.0000
10:95610300:G:C	acceptor_gain	1.0000
10:95610300:G:GC	acceptor_gain	1.0000
10:95611254:A:AC	donor_gain	1.0000
10:95611254:ACCGT:A	donor_gain	1.0000
10:95611255:C:CC	donor_gain	1.0000
10:95611255:CCGT:C	donor_gain	1.0000
10:95611255:CCGTC:C	donor_gain	1.0000
10:95611258:T:TA	donor_gain	1.0000
10:95613736:TCTTA:T	donor_loss	1.0000
10:95613737:CTTAC:C	donor_loss	1.0000
10:95613738:TTAC:T	donor_loss	1.0000
10:95613739:TA:T	donor_loss	1.0000
10:95613741:C:CT	donor_loss	1.0000
10:95614157:TTCAC:T	acceptor_gain	1.0000
10:95614158:TCAC:T	acceptor_gain	1.0000

AlphaMissense

5186 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:95606924:A:C	S742R	1.000
10:95606924:A:T	S742R	1.000
10:95606926:T:G	S742R	1.000
10:95610214:C:T	G730D	1.000
10:95614015:A:C	C584W	1.000
10:95614106:A:G	L554P	1.000
10:95633579:A:G	L210P	1.000
10:95637157:C:T	G165E	1.000
10:95637158:C:G	G165R	1.000
10:95637158:C:T	G165R	1.000
10:95637163:G:T	A163D	1.000
10:95637372:C:A	G123V	1.000
10:95637372:C:T	G123D	1.000
10:95637373:C:G	G123R	1.000
10:95637389:A:C	S117R	1.000
10:95637389:A:T	S117R	1.000
10:95637391:T:G	S117R	1.000
10:95606866:A:G	W762R	0.999
10:95606866:A:T	W762R	0.999
10:95606901:C:T	G750E	0.999
10:95606902:C:G	G750R	0.999
10:95606902:C:T	G750R	0.999
10:95606931:C:T	G740E	0.999
10:95606932:C:G	G740R	0.999
10:95606932:C:T	G740R	0.999
10:95606937:T:A	E738V	0.999
10:95610214:C:A	G730V	0.999
10:95610215:C:A	G730C	0.999
10:95610215:C:G	G730R	0.999
10:95610216:A:C	D729E	0.999

dbSNP variants (sampled 300 via entrez): RS1000034476 (10:95625507 T>C,G), RS1000208363 (10:95645507 G>A), RS1000239587 (10:95645790 C>A,G), RS1000274342 (10:95625152 T>C), RS1000355243 (10:95646118 T>C), RS1000402668 (10:95619157 C>G), RS1000465631 (10:95639584 T>C), RS1000506464 (10:95619959 G>A), RS1000525412 (10:95650379 C>T), RS1000554374 (10:95638600 G>A,C), RS1000590412 (10:95651754 C>A,T), RS1000679786 (10:95612318 G>A), RS1000749982 (10:95625511 C>T), RS1000810870 (10:95619489 A>C), RS1000916018 (10:95643598 A>G)

Disease associations

OMIM: gene MIM:138250 | disease phenotypes: MIM:616586, MIM:616603, MIM:303350, MIM:613502, MIM:601162, MIM:219150, MIM:616583, MIM:270800

GenCC curated gene-disease

Disease	Classification	Inheritance
ALDH18A1-related de Barsy syndrome	Definitive	Autosomal recessive
autosomal recessive complex spastic paraplegia type 9B	Definitive	Autosomal dominant
cutis laxa, autosomal dominant 3	Definitive	Autosomal dominant
P5CS deficiency	Definitive	Semidominant
hereditary spastic paraplegia	Strong	Semidominant
hereditary spastic paraplegia 9A	Moderate	Semidominant
autosomal dominant complex spastic paraplegia type 9B	Supportive	Autosomal dominant
autosomal dominant cutis laxa	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
P5CS deficiency	Definitive	SD

Mondo (17): autosomal recessive complex spastic paraplegia type 9B (MONDO:0014702), cutis laxa, autosomal dominant 3 (MONDO:0014706), autosomal dominant spastic paraplegia type 9 (MONDO:0015091), de Barsy syndrome (MONDO:0017569), intellectual disability (MONDO:0001071), hearing loss disorder (MONDO:0005365), hereditary spastic paraplegia (MONDO:0019064), agammaglobulinemia 4, autosomal recessive (MONDO:0013289), hereditary spastic paraplegia 9A (MONDO:0011006), ALDH18A1-related de Barsy syndrome (MONDO:0009053), P5CS deficiency (MONDO:0100126), congenital nervous system disorder (MONDO:0002320), spondyloepiphyseal dysplasia, Stanescu type (MONDO:0014701), hereditary spastic paraplegia 5A (MONDO:0010047), hereditary ataxia (MONDO:0100309)

Orphanet (11): De Barsy syndrome (Orphanet:2962), Autosomal recessive spastic paraplegia type 9B (Orphanet:447760), Autosomal dominant cutis laxa (Orphanet:90348), Hereditary spastic paraplegia (Orphanet:685), OBSOLETE: Autosomal dominant spastic paraplegia type 9 (Orphanet:100990), Autosomal dominant spastic paraplegia type 9A (Orphanet:447753), ALDH18A1-related De Barsy syndrome (Orphanet:35664), Spondyloepiphyseal dysplasia, Stanescu type (Orphanet:459051), Autosomal recessive spastic paraplegia type 5A (Orphanet:100986), Hereditary ataxia (Orphanet:183518), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

184 total (30 of 184 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000012	Urinary urgency
HP:0000015	Bladder diverticulum
HP:0000016	Urinary retention
HP:0000020	Urinary incontinence
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000122	Unilateral renal agenesis
HP:0000160	Narrow mouth
HP:0000239	Large fontanelles
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000270	Delayed cranial suture closure
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000337	Broad forehead
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment
HP:0000411	Protruding ear
HP:0000418	Narrow nasal ridge
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000545	Myopia
HP:0000601	Hypotelorism
HP:0000639	Nystagmus
HP:0000666	Horizontal nystagmus

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003182_4	Staphylococcus aureus nasal carriage (persistent)	2.000000e-06
GCST007045_33	PR interval	4.000000e-16
GCST009391_1304	Metabolite levels	2.000000e-06
GCST010321_126	PR interval	9.000000e-31

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007757	persistent Staphylococcus aureus carrier status
EFO:0004462	PR interval
EFO:0010517	oxalate measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C562627	Cutis Laxa, Autosomal Dominant (supp.)
C535990	De Barsy syndrome (supp.)
C531684	Hereditary spinal ataxia (supp.)
C536868	Spastic paraplegia 9, autosomal dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295784 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

55 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	4
bisphenol A	affects expression, decreases expression	3
sodium arsenite	affects cotreatment, increases expression, decreases expression	3
Acetaminophen	decreases expression	2
Caffeine	decreases expression, increases phosphorylation	2
Cisplatin	decreases expression	2
Tretinoin	affects cotreatment, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
chloroacetaldehyde	affects expression	1
triphenyl phosphate	affects expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
tris(2-butoxyethyl) phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
adefovir dipivoxil	decreases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	decreases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
NSC 689534	affects binding, decreases expression	1
excavatolide B	decreases expression	1
bisphenol AF	increases expression	1
Bortezomib	decreases expression	1
Sunitinib	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118702	Binding	Binding affinity to ALDH18A1 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2RG	Abcam HEK293T ALDH18A1 KO	Transformed cell line	Female
CVCL_D8Z1	Ubigene HEK293 ALDH18A1 KO	Transformed cell line	Female
CVCL_E1Q4	HAP1 ALDH18A1 (-) 2	Cancer cell line	Male
CVCL_E1Q5	HAP1 ALDH18A1 (-) 3	Cancer cell line	Male
CVCL_XL24	HAP1 ALDH18A1 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

351 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding