ALDH18A1

protein-coding

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

Gene summary

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]

Previous symbols:

GSAS
PYCS
SPG9

MANE transcript

NM_002860.4

Inheritance

AR, AD, SD

ClinVar variants

P:81U:453B:171

Top phenotype

Cutis laxa, autosomal dominant 3; Spastic paraplegia 9A, autosomal dominant; Cutis laxa, autosomal recessive, type IIIA; Spastic paraplegia 9B, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr10:95,605,941-95,656,711

External References & Databases

Ensembl (ENSG00000059573)

Transcript & Mutation Effects

hg38 • Region Span ~50.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ALDH18A1-related de Barsy syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009053

Submitter: Orphanet

autosomal dominant cutis laxaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019571

Submitter: Orphanet

hereditary spastic paraplegia 9ASUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011006

Submitter: Orphanet

P5CS deficiencyDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0100126

Submitter: ClinGen

ALDH18A1 was first reported in relation to semidominant P5CS deficiency in 2000. This gene, which encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), was first characterized in a family with autosomal recessive cutis laxa (Baumgartner et al., PMID: 11092761). However, more recently it has been implicated in both autosomal dominant and resessive forms of cutis laxa and spastic paraplegia (PMIDs: 26026163, 26320891). At least fifteen unique variants (e.g. missense, nonsense, frameshift, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, significant segregation data, and experimental data. Variants in this gene have been reported in at least seventeen probands in seven publications (PMIDs: 11092761, 21739576, 24913064, 26026163, 26297558, 26320891, 28228640). Variants in this gene also segregated with the disorder in over twenty-five additional family members, the majority of which were confirmed via whole exome sequencing. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is a variable loss-of-function, depending on the specific mutation(s) present. ALDH18A1 variants fall on a spectrum of severity based on the amount of P5CS residual activity, ranging from the less severe dominant negative missense variants (AD cutis laxa/AD spastic paraplegia) to the highly severe null or grossly misfolded variants that show little to no activity (AR cutis laxa/AR spastic paraplegia) (Marco-Marin et al., 2020; PMID: 32017139). This gene-disease association is additionally supported by a limited amount of experimental evidence. P5CS is a crucial enzyme in several amino acid pathways, catalyzing the de novo biosynthesis of proline, ornithine, and arginine by converting glutamate into P5C. This function additionally matches the probands' metabolic phenotype, commonly consisting of hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and/or hypoprolinemia. A similar function is shared by PYRC1, an enzyme that catalyzes the last step in proline synthesis and is established as a causative agent in de Barsy syndrome (AKA AR Cutis Laxa Type III). Immunoflorescent analysis of skin fibroblast mitochondria additionally demonstrates colocalization of PYCR1 and P5CS (PMID: 19648921). In summary, ALDH18A1 is definitively associated with semidominant P5CS deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

autosomal dominant complex spastic paraplegia type 9BSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018644

Submitter: Orphanet

hereditary spastic paraplegia 9AMODERATE

Inheritance Pattern: SD

Disease ID:MONDO:0011006

Submitter: Ambry Genetics

ALDH18A1-related de Barsy syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009053

Submitter: Ambry Genetics

ALDH18A1-related de Barsy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009053

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive complex spastic paraplegia type 9BDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014702

Submitter: G2P

autosomal recessive complex spastic paraplegia type 9BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014702

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive complex spastic paraplegia type 9BSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014702

Submitter: Labcorp Genetics (formerly Invitae)

cutis laxa, autosomal dominant 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014706

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive complex spastic paraplegia type 9BSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014702

Submitter: Orphanet

cutis laxa, autosomal dominant 3MODERATE

Inheritance Pattern: SD

Disease ID:MONDO:0014706

Submitter: Ambry Genetics

autosomal recessive complex spastic paraplegia type 9BLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014702

Submitter: G2P

cutis laxa, autosomal dominant 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014706

Submitter: PanelApp Australia

hereditary spastic paraplegiaSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0019064

Submitter: PanelApp Australia

ALDH18A1-related de Barsy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009053

Submitter: PanelApp Australia

P5CS deficiencyDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0100126

Submitter: Illumina

cutis laxa, autosomal dominant 3DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014706

Submitter: G2P

ALDH18A1-related de Barsy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009053

Submitter: Genomics England PanelApp

ALDH18A1-related de Barsy syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009053

Submitter: G2P

cutis laxa, autosomal dominant 3MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014706

Submitter: Ambry Genetics

ALDH18A1-related de Barsy syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0009053

Submitter: Ambry Genetics

cutis laxa, autosomal dominant 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014706

Submitter: Genomics England PanelApp

autosomal recessive complex spastic paraplegia type 9BLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014702

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Cutis laxa, autosomal dominant 3; Spastic paraplegia 9A, autosomal dominant; Cutis laxa, autosomal recessive, type IIIA; Spastic paraplegia 9B, autosomal recessiveAD/AR

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: 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

Refs: 9643297; 11092761; 18478038; 21739576; 24913064; 26026163; 26297558; 26320891

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALDH18A1 variants in ClinVar

20 Conditions Cataloged

Cutis laxa, autosomal dominant 3Total: 627

de Barsy syndromeTotal: 613

Autosomal dominant spastic paraplegia type 9Total: 610

not providedTotal: 286

ALDH18A1-related de Barsy syndromeTotal: 83

Inborn genetic diseasesTotal: 72

ALDH18A1-related disorderTotal: 63

not specifiedTotal: 62

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002860.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			15 clinvar	152 clinvar	2 clinvar	169
missense	11 clinvar	27 clinvar	430 clinvar	16 clinvar		484
nonsense	7 clinvar	8 clinvar	3 clinvar			18
start loss						0
frameshift	10 clinvar	5 clinvar				15
splice donor/acceptor (+/-2bp)	3 clinvar	10 clinvar	5 clinvar	1 clinvar		19
Total	31	50	453	169	2	705

Highest pathogenic variant AF is 0.00003780962

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 62 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002860.4	RefSeq	NP_002851.2	17	MANE Select
ENST00000371224.7	Ensembl	ENSP00000360268.2	17	MANE Select
NM_001017423.2	RefSeq	NP_001017423.1	17	Standard
NM_001323412.2	RefSeq	NP_001310341.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Arginine and proline metabolism - Homo sapiens (human)
Amino Acid metabolism
Urea cycle and metabolism of amino groups
Metabolism of amino acids and derivatives
Metabolism

Biological Process

glutamate metabolic process
proline biosynthetic process
ornithine biosynthetic process
cellular amino acid biosynthetic process
phosphorylation

Molecular Function

RNA binding
glutamate 5-kinase activity
glutamate-5-semialdehyde dehydrogenase activity
protein binding
ATP binding

Cellular Component

mitochondrion
mitochondrial inner membrane
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371224
Coding exons: 17
Length: 50768
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 125748
p: 0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.97	325	441	0.737	0.0000277	5169
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.463

Intolerance Scores

LoFtool: 0.544
RVIS EVS: -0.93
RVIS percentile EVS: 9.61

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.990

Gene Damage Prediction

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