P5CS deficiency

Summary

P5CS deficiency (MONDO:0100126) is a disease caused by ALDH18A1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ALDH18A1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	P5CS deficiency
Mondo ID	MONDO:0100126
GARD	0026056
Is cancer (heuristic)	no

Also known as: delta1-pyrroline-5-carboxylate synthetase deficiency · P5CS deficiency

Data availability: 5 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn disorder of proline metabolism › P5CS deficiency

Related subtypes (2): autosomal recessive cutis laxa type 2, hyperprolinemia

Subtypes (4): ALDH18A1-related de Barsy syndrome, autosomal recessive complex spastic paraplegia type 9B, cutis laxa, autosomal dominant 3, autosomal dominant spastic paraplegia type 9

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

5 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
217117	NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)	ALDH18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
217116	NM_002860.4(ALDH18A1):c.727G>C (p.Val243Leu)	ALDH18A1	Likely pathogenic	criteria provided, single submitter
1190002	NM_002860.4(ALDH18A1):c.1367G>A (p.Arg456His)	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1676223	NM_002860.4(ALDH18A1):c.304-8A>G	ALDH18A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3779373	NM_002860.4(ALDH18A1):c.1454A>G (p.Asp485Gly)	ALDH18A1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ALDH18A1	Definitive	Semidominant	P5CS deficiency	25

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALDH18A1	Orphanet:35664	ALDH18A1-related De Barsy syndrome
ALDH18A1	Orphanet:447753	Autosomal dominant spastic paraplegia type 9A
ALDH18A1	Orphanet:447757	Autosomal dominant spastic paraplegia type 9B
ALDH18A1	Orphanet:447760	Autosomal recessive spastic paraplegia type 9B
ALDH18A1	Orphanet:90348	Autosomal dominant cutis laxa

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALDH18A1	HGNC:9722	ENSG00000059573	P54886	Delta-1-pyrroline-5-carboxylate synthase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALDH18A1	Delta-1-pyrroline-5-carboxylate synthase	Bifunctional enzyme that converts glutamate to glutamate 5-semialdehyde, an intermediate in the biosynthesis of proline, ornithine and arginine.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALDH18A1	Kinase	yes		GPR_dom, Asp/Glu/Uridylate_kinase, Glu/AcGlu_kinase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	1
jejunal mucosa	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALDH18A1	263	ubiquitous	marker	parotid gland, jejunal mucosa, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH18A1	7,351

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALDH18A1	P54886	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glutamate and glutamine metabolism	1	815.7×	0.002	ALDH18A1
Mitochondrial protein degradation	1	114.2×	0.009	ALDH18A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
L-ornithine biosynthetic process	1	16852.0×	3e-04	ALDH18A1
L-citrulline biosynthetic process	1	4213.0×	6e-04	ALDH18A1
L-proline biosynthetic process	1	2808.7×	6e-04	ALDH18A1
response to temperature stimulus	1	1532.0×	8e-04	ALDH18A1
glutamate metabolic process	1	1123.5×	9e-04	ALDH18A1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALDH18A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ALDH18A1	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ALDH18A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ALDH18A1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.