5-oxoprolinase deficiency

Summary

5-oxoprolinase deficiency (MONDO:0009825) is a disease caused by OPLAH (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: OPLAH (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 430
• Phenotypes (HPO): 19

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0040142	Reduced circulating 5-oxoprolinase activity	Very frequent (80-99%)
HP:0410132	Increased level of L-pyroglutamic acid in urine	Very frequent (80-99%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)
HP:0008947	Floppy infant	Occasional (5-29%)
HP:0100786	Hypersomnia	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0000787	Nephrolithiasis	Occasional (5-29%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001942	Metabolic acidosis	Occasional (5-29%)
HP:0001943	Hypoglycemia	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0004387	Enterocolitis	Occasional (5-29%)
HP:0005490	Postnatal macrocephaly	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	5-oxoprolinase deficiency
Mondo ID	MONDO:0009825
MeSH	C535322
OMIM	260005
Orphanet	33572
SNOMED CT	26132002
UMLS	C0268525
MedGen	82814
GARD	0005681
Is cancer (heuristic)	no

Also known as: 5-alpha-oxoprolinase deficiency · 5-oxoprolinase deficiency · 5-oxoprolinase deficiency (disease) · inborn 5-oxoprolinase (ATP-hydrolyzing) activity disorder · inborn error of 5-oxoprolinase (ATP-hydrolyzing) activity · OPLAHD · oxoprolinuria due to oxoprolinase deficiency · rare inborn error of 5-oxoprolinase (ATP-hydrolyzing) activity

Data availability: 430 ClinVar variants · 3 GenCC gene-disease records · 1 HPO phenotype.

Disease family

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 the gamma-glutamyl cycle › inherited glutathione metabolism disease › 5-oxoprolinase deficiency

Related subtypes (5): gamma-glutamylcysteine synthetase deficiency, gamma-glutamyl transpeptidase deficiency, spondylometaphyseal dysplasia, Sedaghatian type, inherited glutathione synthetase deficiency, hemolytic anemia due to glutathione reductase deficiency

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

430 retrieved; paginated sample, class counts are floors:

180 likely benign, 145 uncertain significance, 44 benign, 20 pathogenic, 19 likely pathogenic, 11 benign/likely benign, 9 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1179038	NM_017570.5(OPLAH):c.313_316del (p.Arg105fs)	OPLAH	Pathogenic	criteria provided, multiple submitters, no conflicts
1179092	NM_017570.5(OPLAH):c.2076C>A (p.Cys692Ter)	OPLAH	Pathogenic	criteria provided, single submitter
1459596	NM_017570.5(OPLAH):c.3016C>T (p.Gln1006Ter)	OPLAH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2037024	NM_017570.5(OPLAH):c.206_251dup (p.Thr85fs)	OPLAH	Pathogenic	criteria provided, single submitter
2194554	NM_017570.5(OPLAH):c.3612C>G (p.Tyr1204Ter)	OPLAH	Pathogenic	criteria provided, single submitter
2770865	NM_017570.5(OPLAH):c.2677C>T (p.Gln893Ter)	OPLAH	Pathogenic	criteria provided, single submitter
2776954	NM_017570.5(OPLAH):c.2362dup (p.His788fs)	OPLAH	Pathogenic	criteria provided, single submitter
2835035	NM_017570.5(OPLAH):c.1652del (p.Leu551fs)	OPLAH	Pathogenic	criteria provided, single submitter
2870863	NM_017570.5(OPLAH):c.2669del (p.Gly890fs)	OPLAH	Pathogenic	criteria provided, single submitter
3017064	NM_017570.5(OPLAH):c.3249_3250delinsTT (p.Gln1084Ter)	OPLAH	Pathogenic	criteria provided, single submitter
31133	NM_017570.5(OPLAH):c.2608dup (p.His870fs)	OPLAH	Pathogenic	criteria provided, multiple submitters, no conflicts
3600351	NM_017570.5(OPLAH):c.3081dup (p.Arg1028fs)	OPLAH	Pathogenic	criteria provided, single submitter
3600352	NM_017570.5(OPLAH):c.3701C>A (p.Ser1234Ter)	OPLAH	Pathogenic	criteria provided, single submitter
3607909	NM_017570.5(OPLAH):c.3457_3458del (p.Ser1153fs)	OPLAH	Pathogenic	criteria provided, single submitter
3670809	NM_017570.5(OPLAH):c.3187C>T (p.Arg1063Ter)	OPLAH	Pathogenic	criteria provided, single submitter
39635	NM_017570.5(OPLAH):c.969C>A (p.Ser323Arg)	OPLAH	Pathogenic	no assertion criteria provided
4716570	NM_017570.5(OPLAH):c.975del (p.Arg324_Tyr325insTer)	OPLAH	Pathogenic	criteria provided, single submitter
4733188	NM_017570.5(OPLAH):c.1336_1337del (p.Ser446fs)	OPLAH	Pathogenic	criteria provided, single submitter
572337	NM_017570.5(OPLAH):c.2557C>T (p.Arg853Ter)	OPLAH	Pathogenic	criteria provided, single submitter
856398	NM_017570.5(OPLAH):c.493C>T (p.Gln165Ter)	OPLAH	Pathogenic	criteria provided, single submitter
861806	NM_017570.5(OPLAH):c.587+1G>A	OPLAH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
955289	NM_017570.5(OPLAH):c.2987dup (p.Arg997fs)	OPLAH	Pathogenic	criteria provided, single submitter
1324831	NM_017570.5(OPLAH):c.893C>G (p.Ser298Ter)	OPLAH	Likely pathogenic	criteria provided, single submitter
191344	NM_017570.5(OPLAH):c.2303G>A (p.Arg768His)	OPLAH	Likely pathogenic	criteria provided, single submitter
2432374	NM_017570.5(OPLAH):c.3019-2A>G	OPLAH	Likely pathogenic	criteria provided, single submitter
2690662	NM_017570.5(OPLAH):c.169C>T (p.Gln57Ter)	OPLAH	Likely pathogenic	criteria provided, single submitter
2690663	NM_017570.5(OPLAH):c.2686+1G>T	OPLAH	Likely pathogenic	criteria provided, single submitter
3254835	NM_017570.5(OPLAH):c.3394G>T (p.Gly1132Trp)	OPLAH	Likely pathogenic	criteria provided, single submitter
3595431	NM_017570.5(OPLAH):c.3427dup (p.Thr1143fs)	OPLAH	Likely pathogenic	criteria provided, single submitter
3595432	NM_017570.5(OPLAH):c.3168dup (p.Val1057fs)	OPLAH	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
OPLAH	Strong	Autosomal recessive	5-oxoprolinase deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
OPLAH	Orphanet:33572	5-oxoprolinase deficiency

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
OPLAH	HGNC:8149	ENSG00000178814	O14841	5-oxoprolinase	gencc,clinvar
MIR6846	HGNC:50026	ENSG00000277888		microRNA 6846	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
OPLAH	5-oxoprolinase	Catalyzes the cleavage of 5-oxo-L-proline to form L-glutamate coupled to the hydrolysis of ATP to ADP and inorganic phosphate.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
OPLAH	Enzyme (other)	yes	3.5.2.9	Hydantoinase_A, Hydantoinase_B, Hydant_A_N
MIR6846	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	2
left testis	1
right testis	1
blood	1
muscle of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
OPLAH	217	ubiquitous	marker	apex of heart, right testis, left testis
MIR6846	62		yes	apex of heart, muscle of leg, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
OPLAH	1,204
MIR6846	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OPLAH	O14841	88.08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 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
Defective OPLAH causes OPLAHD	1	11420.0×	2e-04	OPLAH
Glutathione synthesis and recycling	1	951.7×	0.001	OPLAH

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
glutathione metabolic process	1	351.1×	0.003	OPLAH

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
OPLAH	0	0
MIR6846	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
OPLAH	3.5.2.9	5-oxoprolinase (ATP-hydrolysing)

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	0
D	Druggable family + AlphaFold only, no drug	1	OPLAH
E	Difficult family or no structure, no drug	1	MIR6846

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
OPLAH	0	—
MIR6846	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.