ALDH18A1

aldehyde dehydrogenase 18 family member A1, the group of Aldehyde dehydrogenases

Basic information

Region (hg38): 10:95605941-95656711

Previous symbols: [ "GSAS", "PYCS", "SPG9" ]

Links

ENSG00000059573 ∙ NCBI:5832 ∙ OMIM:138250 ∙ HGNC:9722 ∙ Uniprot:P54886 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• cutis laxa, autosomal dominant 3 (Definitive), mode of inheritance: AD
• cutis laxa, autosomal dominant 3 (Strong), mode of inheritance: AD
• ALDH18A1-related de Barsy syndrome (Strong), mode of inheritance: AR
• ALDH18A1-related de Barsy syndrome (Moderate), mode of inheritance: AR
• cutis laxa, autosomal dominant 3 (Moderate), mode of inheritance: AD
• ALDH18A1-related de Barsy syndrome (Moderate), mode of inheritance: AD
• autosomal recessive complex spastic paraplegia type 9B (Limited), mode of inheritance: AR
• hereditary spastic paraplegia 9A (Moderate), mode of inheritance: Semidominant
• cutis laxa, autosomal dominant 3 (Moderate), mode of inheritance: Semidominant
• ALDH18A1-related de Barsy syndrome (Definitive), mode of inheritance: AR
• ALDH18A1-related de Barsy syndrome (Supportive), mode of inheritance: AR
• autosomal dominant cutis laxa (Supportive), mode of inheritance: AD
• hereditary spastic paraplegia 9A (Supportive), mode of inheritance: AD
• autosomal dominant complex spastic paraplegia type 9B (Supportive), mode of inheritance: AD
• autosomal recessive complex spastic paraplegia type 9B (Supportive), mode of inheritance: AR
• P5CS deficiency (Definitive), mode of inheritance: Semidominant
• autosomal recessive complex spastic paraplegia type 9B (Limited), mode of inheritance: AR
• cutis laxa, autosomal dominant 3 (Strong), mode of inheritance: AD
• ALDH18A1-related de Barsy syndrome (Strong), mode of inheritance: AR
• autosomal recessive complex spastic paraplegia type 9B (Strong), mode of inheritance: AD
• autosomal recessive complex spastic paraplegia type 9B (Strong), mode of inheritance: AR
• P5CS deficiency (Definitive), mode of inheritance: Semidominant
• autosomal recessive complex spastic paraplegia type 9B (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cutis laxa, autosomal dominant 3; Spastic paraplegia 9A, autosomal dominant; Cutis laxa, autosomal recessive, type IIIA; Spastic paraplegia 9B, autosomal recessive	AD/AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Ophthalmologic	9643297; 11092761; 18478038; 21739576; 24913064; 26026163; 26297558; 26320891

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ALDH18A1 gene.

• Cutis_laxa,_autosomal_dominant_3 (541 variants)
• de_Barsy_syndrome (530 variants)
• Autosomal_dominant_spastic_paraplegia_type_9 (527 variants)
• not_provided (242 variants)
• ALDH18A1-related_de_Barsy_syndrome (77 variants)
• Inborn_genetic_diseases (53 variants)
• ALDH18A1-related_disorder (41 variants)
• Hereditary_spastic_paraplegia_9A (33 variants)
• Autosomal_recessive_complex_spastic_paraplegia_type_9B (33 variants)
• Hereditary_spastic_paraplegia (23 variants)
• not_specified (20 variants)
• Intellectual_disability (5 variants)
• P5CS_deficiency (4 variants)
• ALDH18A1_deficiency (3 variants)
• Spondyloepiphyseal_dysplasia,_Stanescu_type (2 variants)
• Cutis_Laxa,_Recessive (1 variants)
• Hereditary_spastic_paraplegia_5A (1 variants)
• Hearing_impairment (1 variants)
• See_cases (1 variants)
• Hereditary_ataxia (1 variants)
• Abnormality_of_the_nervous_system (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ALDH18A1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000002860.4. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			12	126	1	139
missense	11	25	366	12	1	415
nonsense	6	6	1			13
start loss						0
frameshift	10	3				13
splice donor/acceptor (+/-2bp)	4	5	2	1		12
Total	31	39	381	139	2

Highest pathogenic variant AF is 0.00003780962

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ALDH18A1	protein_coding	protein_coding	ENST00000371224	17	50768

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000812	0.999	125722	0	26	125748	0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.97	325	441	0.737	0.0000277	5169
Missense in Polyphen		142	226.98	0.62562		2645
Synonymous	0.477	158	166	0.953	0.00000995	1610
Loss of Function	3.94	13	39.8	0.326	0.00000249	448

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000152	0.000152
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000150	0.000149
Middle Eastern	0.0000544	0.0000544
South Asian	0.000131	0.000131
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Bifunctional enzyme that converts glutamate to glutamate 5-semialdehyde, an intermediate in the biosynthesis of proline, ornithine and arginine. {ECO:0000269|PubMed:10037775, ECO:0000269|PubMed:11092761, ECO:0000269|PubMed:26297558, ECO:0000269|PubMed:26320891}.
• Disease: DISEASE: 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. {ECO:0000269|PubMed:11092761, ECO:0000269|PubMed:18478038, ECO:0000269|PubMed:22170564, ECO:0000269|PubMed:24767728}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:26320891}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:26026163, ECO:0000269|PubMed:26297558}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:26026163}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Arginine and proline metabolism - Homo sapiens (human);Amino Acid metabolism;Urea cycle and metabolism of amino groups;Metabolism of amino acids and derivatives;Metabolism;ornithine <i>de novo </i> biosynthesis;Urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine;proline biosynthesis;Amino acid synthesis and interconversion (transamination) (Consensus)

Recessive Scores

• pRec: 0.463

Intolerance Scores

• loftool: 0.544
• rvis_EVS: -0.93
• rvis_percentile_EVS: 9.61

Haploinsufficiency Scores

• pHI: 0.294
• hipred: Y
• hipred_score: 0.618
• ghis: 0.646

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.990

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Aldh18a1

Gene ontology

• Biological process: glutamate metabolic process;proline biosynthetic process;ornithine biosynthetic process;cellular amino acid biosynthetic process;phosphorylation;citrulline biosynthetic process;oxidation-reduction process;L-proline biosynthetic process
• Cellular component: mitochondrion;mitochondrial inner membrane;cytosol
• Molecular function: RNA binding;glutamate 5-kinase activity;glutamate-5-semialdehyde dehydrogenase activity;protein binding;ATP binding;delta1-pyrroline-5-carboxylate synthetase activity;identical protein binding