Dihydropyrimidinuria

Summary

Dihydropyrimidinuria (MONDO:0009111) is a disease caused by DPYS (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DPYS (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 66
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0012127	Uraciluria	Frequent (30-79%)
HP:6000118	Elevated urinary dihydrouracil level	Frequent (30-79%)
HP:6000119	Elevated urinary dihydrothymine level	Frequent (30-79%)
HP:6000331	Elevated urinary thymine level	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000280	Coarse facial features	Occasional (5-29%)
HP:0000717	Autism	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0011473	Villous atrophy	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0012758	Neurodevelopmental delay	Occasional (5-29%)
HP:0002376	Developmental regression	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dihydropyrimidinuria
Mondo ID	MONDO:0009111
OMIM	222748
Orphanet	38874
DOID	DOID:0111629
SNOMED CT	238014002
UMLS	C0342803
MedGen	83353
GARD	0012347
Is cancer (heuristic)	no

Also known as: dihydropyrimidinase deficiency · dihydropyrimidinuria · DPYSD

Data availability: 66 ClinVar variants · 3 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 › dihydropyrimidinuria

Related subtypes (8): hyper-beta-alaninemia, orotic aciduria, 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

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

66 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 12 benign, 9 pathogenic, 7 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 5 likely pathogenic, 4 benign/likely benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029334	NM_001385.3(DPYS):c.1468C>T (p.Arg490Cys)	DPYS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1360900	NM_001385.3(DPYS):c.568C>T (p.Gln190Ter)	DPYS	Pathogenic	criteria provided, multiple submitters, no conflicts
1453274	NM_001385.3(DPYS):c.1217G>A (p.Trp406Ter)	DPYS	Pathogenic	criteria provided, multiple submitters, no conflicts
184	NM_001385.3(DPYS):c.1001A>G (p.Gln334Arg)	DPYS	Pathogenic	criteria provided, multiple submitters, no conflicts
185	NM_001385.3(DPYS):c.1303G>A (p.Gly435Arg)	DPYS	Pathogenic	no assertion criteria provided
186	NM_001385.3(DPYS):c.1078T>C (p.Trp360Arg)	DPYS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
187	NM_001385.3(DPYS):c.1235G>T (p.Arg412Met)	DPYS	Pathogenic	no assertion criteria provided
2191880	NM_001385.3(DPYS):c.253C>T (p.Gln85Ter)	DPYS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2682641	NM_001385.3(DPYS):c.502T>C (p.Tyr168His)	DPYS	Pathogenic	no assertion criteria provided
372797	NM_001385.3(DPYS):c.1137C>A (p.Ser379Arg)	DPYS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3902332	NM_001385.3(DPYS):c.904C>T (p.Arg302Ter)	DPYS	Pathogenic	criteria provided, single submitter
446083	NM_001385.3(DPYS):c.1423C>T (p.Arg475Ter)	DPYS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
863103	NM_001385.3(DPYS):c.1393C>T (p.Arg465Ter)	DPYS	Pathogenic	criteria provided, multiple submitters, no conflicts
909729	NM_001385.3(DPYS):c.1469G>A (p.Arg490His)	DPYS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
972740	NM_001385.3(DPYS):c.175G>T (p.Val59Phe)	DPYS	Pathogenic	no assertion criteria provided
2691719	NM_001385.3(DPYS):c.1064G>A (p.Arg355Gln)	DPYS	Likely pathogenic	criteria provided, single submitter
2691788	NM_001385.3(DPYS):c.983G>T (p.Cys328Phe)	DPYS	Likely pathogenic	criteria provided, single submitter
2735195	NM_001385.3(DPYS):c.1092+5del	DPYS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4081351	NM_001385.3(DPYS):c.14C>A (p.Ser5Ter)	DPYS	Likely pathogenic	criteria provided, single submitter
631543	NM_001385.3(DPYS):c.905G>A (p.Arg302Gln)	DPYS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
100132	NM_001385.3(DPYS):c.1506del (p.Arg503fs)	DPYS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
100147	NM_001385.3(DPYS):c.264+5C>T	DPYS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2055236	NM_001385.3(DPYS):c.209T>C (p.Met70Thr)	DPYS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
377800	NM_001385.3(DPYS):c.352C>T (p.Arg118Ter)	DPYS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
908926	NM_001385.3(DPYS):c.342C>T (p.Phe114=)	DPYS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
908927	NM_001385.3(DPYS):c.264+10C>T	DPYS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
908928	NM_001385.3(DPYS):c.177C>G (p.Val59=)	DPYS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1333583	NM_001385.3(DPYS):c.1027A>G (p.Thr343Ala)	DPYS	Uncertain significance	criteria provided, multiple submitters, no conflicts
361441	NM_001385.3(DPYS):c.*408A>G	DPYS	Uncertain significance	criteria provided, single submitter
361444	NM_001385.3(DPYS):c.*205G>A	DPYS	Uncertain significance	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
DPYS	Strong	Autosomal recessive	dihydropyrimidinuria	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DPYS	Orphanet:38874	Dihydropyrimidinuria

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
DPYS	HGNC:3013	ENSG00000147647	Q14117	Dihydropyrimidinase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DPYS	Dihydropyrimidinase	Catalyzes the second step of the reductive pyrimidine degradation, the reversible hydrolytic ring opening of dihydropyrimidines.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DPYS	Other/Unknown	no		Amidohydro-rel, Metal-dep_hydrolase_composite, Hydantoinase/dihydroPyrase

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
DPYS	175	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
DPYS	1,468

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DPYS	Q14117	1

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 catabolism	1	878.5×	0.001	DPYS

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
pyrimidine nucleobase catabolic process	1	8426.0×	4e-04	DPYS
uracil catabolic process	1	8426.0×	4e-04	DPYS
thymine catabolic process	1	5617.3×	4e-04	DPYS
CMP catabolic process	1	2106.5×	5e-04	DPYS
UMP catabolic process	1	2106.5×	5e-04	DPYS
dCMP catabolic process	1	1872.4×	5e-04	DPYS
dUMP catabolic process	1	1872.4×	5e-04	DPYS

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
DPYS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	1	DPYS

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)
DPYS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.