Orotic aciduria

Summary

Orotic aciduria (MONDO:0009797) is a disease caused by UMPS (GenCC Definitive), with 1 cohort gene and 1 clinical trial. Top therapeutic interventions include uridine triacetate.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: UMPS (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 5
• Phenotypes (HPO): 16
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0003218	Oroticaciduria	Very frequent (80-99%)
HP:0003355	Aminoaciduria	Very frequent (80-99%)
HP:0003526	Orotic acid crystalluria	Very frequent (80-99%)
HP:0000069	Abnormality of the ureter	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000494	Downslanted palpebral fissures	Frequent (30-79%)
HP:0001385	Hip dysplasia	Frequent (30-79%)
HP:0001643	Patent ductus arteriosus	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0008388	Abnormal toenail morphology	Frequent (30-79%)
HP:0011840	Abnormality of T cell physiology	Frequent (30-79%)
HP:0000358	Posteriorly rotated ears	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	orotic aciduria
Mondo ID	MONDO:0009797
OMIM	258900
Orphanet	30
DOID	DOID:0050833
ICD-11	449856959
NCIT	C98944
SNOMED CT	47641009
UMLS	C0220987
MedGen	472940
GARD	0005429
MedDRA	10052621
NORD	1942
Is cancer (heuristic)	no

Also known as: Hereditary Orotic Aciduria · orotate phosphoribosyltransferase and OMP decarboxylase deficiency · orotic aciduria · orotic aciduria II (formerly) · orotic aciduria type 1 · orotic aciduria without megaloblastic Anaemia · oroticaciduria · oroticaciduria 1 · orotidylic decarboxylase deficiency · UMP synthtase deficiency · UMPS · uridine monophosphate synthetase deficiency

Data availability: 5 ClinVar variants · 6 GenCC gene-disease records · 3 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of purine or pyrimidine metabolism › inborn disorder of pyrimidine metabolism › orotic aciduria

Related subtypes (8): dihydropyrimidinuria, hyper-beta-alaninemia, hemolytic anemia due to pyrimidine 5’ nucleotidase deficiency, dihydropyrimidine dehydrogenase deficiency, mitochondrial DNA depletion syndrome, myopathic form, beta-ureidopropionase deficiency, developmental and epileptic encephalopathy, 50, mitochondrial neurogastrointestinal encephalomyopathy

Subtypes (1): orotic aciduria without megaloblastic anemia

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, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
342930	NM_000373.4(UMPS):c.857T>A (p.Ile286Asn)	UMPS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
632395	NM_000373.4(UMPS):c.385G>T (p.Gly129Ter)	UMPS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1022377	NM_000373.4(UMPS):c.254T>C (p.Ile85Thr)	UMPS	Uncertain significance	criteria provided, multiple submitters, no conflicts
3899230	NM_000373.4(UMPS):c.866A>G (p.Asp289Gly)	UMPS	Uncertain significance	criteria provided, single submitter
943262	NM_000373.4(UMPS):c.1063C>A (p.Gln355Lys)	UMPS	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
UMPS	Definitive	Autosomal recessive	orotic aciduria	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UMPS	Orphanet:30	Hereditary orotic aciduria

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
UMPS	HGNC:12563	ENSG00000114491	P11172	Uridine 5’-monophosphate synthase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UMPS	Uridine 5’-monophosphate synthase	Bifunctional enzyme catalyzing the last two steps of de novo pyrimidine biosynthesis, orotate phosphoribosyltransferase (OPRT), which converts orotate to orotidine-5’-monophosphate (OMP), and orotidine-5’-monophosphate decarboxylase (ODC),…

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
UMPS	Enzyme (other)	yes	4.1.1.23	PRTase_dom, OMPdeCOase_dom, Or_phspho_trans_dom

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
adrenal tissue	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UMPS	279	ubiquitous	marker	adrenal tissue, ventricular zone, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UMPS	4,760

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UMPS	P11172	72

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Pyrimidine biosynthesis	1	3806.7×	3e-04	UMPS

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
UMP biosynthetic process	1	8426.0×	3e-04	UMPS
pyrimidine nucleobase biosynthetic process	1	5617.3×	3e-04	UMPS
‘de novo’ UMP biosynthetic process	1	5617.3×	3e-04	UMPS
UDP biosynthetic process	1	3370.4×	4e-04	UMPS
‘de novo’ pyrimidine nucleobase biosynthetic process	1	2808.7×	4e-04	UMPS

Therapeutics

Drug target analysis

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

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
UMPS	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PYRAZOFURIN	2	UMPS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
UMPS	14	Binding:14

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
UMPS	4.1.1.23	orotidine-5’-phosphate decarboxylase

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
PYRAZOFURIN	2	UMPS

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	1	UMPS
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02110147	PHASE3	COMPLETED	Open-Label Study of Uridine Triacetate in Pediatric Patients With Hereditary Orotic Aciduria

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
URIDINE TRIACETATE	4	1