Beta-ureidopropionase deficiency

Summary

Beta-ureidopropionase deficiency (MONDO:0013164) is a disease caused by UPB1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: UPB1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 80
• Phenotypes (HPO): 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	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:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:6000082	Reduced hepatic beta-ureidopropionase activity	Frequent (30-79%)
HP:6000118	Elevated urinary dihydrouracil level	Frequent (30-79%)
HP:6000119	Elevated urinary dihydrothymine level	Frequent (30-79%)
HP:6000279	Elevated urinary N-carbamoyl-beta-alanine level	Frequent (30-79%)
HP:6000623	Elevated urinary N-carbamyl-beta-aminoisobutyric acid level	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000717	Autism	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002539	Cortical dysplasia	Occasional (5-29%)
HP:0012448	Delayed myelination	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	beta-ureidopropionase deficiency
Mondo ID	MONDO:0013164
MeSH	C563210
OMIM	613161
Orphanet	65287
ICD-11	1227425060
SNOMED CT	124511000
UMLS	C1291512
MedGen	226944
GARD	0016669
Is cancer (heuristic)	no

Also known as: Beta-alanine synthase deficiency · beta-ureidopropionase deficiency · UPB1D

Data availability: 80 ClinVar variants · 4 GenCC gene-disease records.

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 purine or pyrimidine metabolism › inborn disorder of pyrimidine metabolism › beta-ureidopropionase deficiency

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

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

80 retrieved; paginated sample, class counts are floors:

31 uncertain significance, 20 conflicting classifications of pathogenicity, 9 benign, 6 pathogenic, 5 likely benign, 3 benign/likely benign, 3 likely pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071875	NM_016327.3(UPB1):c.352C>T (p.Gln118Ter)	UPB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1702976	NM_016327.3(UPB1):c.364+6T>G	UPB1	Pathogenic	no assertion criteria provided
1702980	NM_016327.3(UPB1):c.916+1_916+2dup	UPB1	Pathogenic	no assertion criteria provided
2627297	NM_016327.3(UPB1):c.670C>T (p.Gln224Ter)	UPB1	Pathogenic	criteria provided, single submitter
280025	NM_016327.3(UPB1):c.873+1G>A	UPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3233897	NM_016327.3(UPB1):c.254del (p.Ala85fs)	UPB1	Pathogenic	criteria provided, single submitter
3336289	NC_000022.10:g.(?24891299)(24898182_24906716)del	UPB1	Pathogenic	criteria provided, single submitter
4147	NM_016327.3(UPB1):c.105-2A>G	UPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
445946	NM_016327.3(UPB1):c.917-1G>A	UPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1702978	NM_016327.3(UPB1):c.1034A>T (p.Asn345Ile)	UPB1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3065964	NM_016327.3(UPB1):c.505C>T (p.Arg169Ter)	UPB1	Likely pathogenic	criteria provided, single submitter
977433	NM_016327.3(UPB1):c.148_149dup (p.Asp51fs)	UPB1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1028017	NM_016327.3(UPB1):c.38T>C (p.Leu13Ser)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1695566	NM_016327.3(UPB1):c.357del (p.Ala120fs)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2173567	NM_016327.3(UPB1):c.386C>T (p.Thr129Met)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225511	NM_016327.3(UPB1):c.977G>A (p.Arg326Gln)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
340931	NM_016327.3(UPB1):c.354G>A (p.Gln118=)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
340932	NM_016327.3(UPB1):c.384T>C (p.Cys128=)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
340933	NM_016327.3(UPB1):c.464C>T (p.Ala155Val)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
340934	NM_016327.3(UPB1):c.514G>A (p.Glu172Lys)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4149	NM_016327.3(UPB1):c.254C>A (p.Ala85Glu)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
445652	NM_016327.3(UPB1):c.91G>A (p.Gly31Ser)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
631886	NM_016327.3(UPB1):c.792C>A (p.Ser264Arg)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899538	NM_016327.3(UPB1):c.387G>A (p.Thr129=)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899540	NM_016327.3(UPB1):c.684C>T (p.Ile228=)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900674	NM_016327.3(UPB1):c.792C>T (p.Ser264=)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900676	NM_016327.3(UPB1):c.903A>G (p.Gly301=)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
902290	NM_016327.3(UPB1):c.54G>A (p.Pro18=)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
902357	NM_016327.3(UPB1):c.1071+10C>T	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903159	NM_016327.3(UPB1):c.225G>T (p.Gly75=)	UPB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
UPB1	Strong	Autosomal recessive	beta-ureidopropionase deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UPB1	Orphanet:65287	Beta-ureidopropionase deficiency

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
UPB1	HGNC:16297	ENSG00000100024	Q9UBR1	Beta-ureidopropionase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UPB1	Beta-ureidopropionase	Catalyzes a late step in pyrimidine degradation.

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)
UPB1	Enzyme (other)	yes	3.5.1.6	C-N_Hydrolase, C-N_Hydrolase_sf, Aliph_Amidase/BUP

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
liver	1
nephron tubule	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UPB1	205	tissue_specific	marker	right lobe of liver, liver, nephron tubule

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UPB1	1,576

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UPB1	Q9UBR1	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Nucleotide catabolism	1	1268.9×	0.002	UPB1
Pyrimidine catabolism	1	878.5×	0.002	UPB1
Metabolism of nucleotides	1	300.5×	0.004	UPB1
Metabolism	1	11.6×	0.086	UPB1

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
obsolete beta-alanine biosynthetic process via 3-ureidopropionate	1	16852.0×	3e-04	UPB1
pyrimidine nucleoside catabolic process	1	16852.0×	3e-04	UPB1
CMP catabolic process	1	2106.5×	9e-04	UPB1
UMP catabolic process	1	2106.5×	9e-04	UPB1
dCMP catabolic process	1	1872.4×	9e-04	UPB1
dUMP catabolic process	1	1872.4×	9e-04	UPB1
protein homotetramerization	1	237.3×	0.006	UPB1
liver development	1	221.7×	0.006	UPB1
protein homooligomerization	1	122.1×	0.009	UPB1
in utero embryonic development	1	72.0×	0.014	UPB1

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
UPB1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
UPB1	3.5.1.6	beta-ureidopropionase

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	UPB1
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)
UPB1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.