DPYS

Summary

DPYS (dihydropyrimidinase, HGNC:3013) is a protein-coding gene on chromosome 8q22.3, encoding Dihydropyrimidinase (Q14117). Catalyzes the second step of the reductive pyrimidine degradation, the reversible hydrolytic ring opening of dihydropyrimidines.

Dihydropyrimidinase catalyzes the conversion of 5,6-dihydrouracil to 3-ureidopropionate in pyrimidine metabolism. Dihydropyrimidinase is expressed at a high level in liver and kidney as a major 2.5-kb transcript and a minor 3.8-kb transcript. Defects in the DPYS gene are linked to dihydropyrimidinuria.

Source: NCBI Gene 1807 — RefSeq curated summary.

At a glance

• Gene–disease (curated): dihydropyrimidinuria (Strong, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 238 total — 15 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 45
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_001385

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3013
Approved symbol	DPYS
Name	dihydropyrimidinase
Location	8q22.3
Locus type	gene with protein product
Status	Approved
Aliases	DHPase
Ensembl gene	ENSG00000147647
Ensembl biotype	protein_coding
OMIM	613326
Entrez	1807

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 29 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000351513, ENST00000519217, ENST00000520483, ENST00000520806, ENST00000521372, ENST00000521573, ENST00000521601, ENST00000533874, ENST00000908791, ENST00000908792, ENST00000908793, ENST00000908794, ENST00000908795, ENST00000908796, ENST00000908797, ENST00000908798, ENST00000908799, ENST00000908800, ENST00000908801, ENST00000908802, ENST00000908803, ENST00000908804, ENST00000908805, ENST00000908806, ENST00000908807, ENST00000908808, ENST00000908809, ENST00000908810, ENST00000908811, ENST00000908812, ENST00000908813, ENST00000908814, ENST00000908815, ENST00000908816

RefSeq mRNA: 1 — MANE Select: NM_001385 NM_001385

CCDS: CCDS6302

Canonical transcript exons

ENST00000351513 — 10 exons

Exon	Start	End
ENSE00000981058	104451246	104451404
ENSE00000981059	104447324	104447503
ENSE00000981060	104444248	104444437
ENSE00001087723	104427980	104428121
ENSE00001087724	104429545	104429701
ENSE00001153806	104424247	104424389
ENSE00001394904	104379431	104379843
ENSE00002092993	104466657	104467055
ENSE00003548973	104392784	104392991
ENSE00003614126	104381184	104381314

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 99.26.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.8467 / max 384.9718, expressed in 23 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
94344	0.8467	23

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.26	gold quality
liver	UBERON:0002107	98.58	gold quality
nephron tubule	UBERON:0001231	96.00	gold quality
adult mammalian kidney	UBERON:0000082	95.98	gold quality
kidney epithelium	UBERON:0004819	95.38	gold quality
renal glomerulus	UBERON:0000074	94.22	gold quality
metanephric glomerulus	UBERON:0004736	93.94	gold quality
adult organism	UBERON:0007023	93.15	gold quality
kidney	UBERON:0002113	91.78	gold quality
right adrenal gland cortex	UBERON:0035827	91.66	gold quality
left adrenal gland cortex	UBERON:0035825	90.49	gold quality
right adrenal gland	UBERON:0001233	90.31	gold quality
left adrenal gland	UBERON:0001234	90.27	gold quality
adrenal cortex	UBERON:0001235	88.64	gold quality
cortex of kidney	UBERON:0001225	86.61	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.05	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.72	gold quality
adrenal gland	UBERON:0002369	84.61	gold quality
mucosa of paranasal sinus	UBERON:0005030	84.52	gold quality
gall bladder	UBERON:0002110	82.35	gold quality
metanephros	UBERON:0000081	82.24	gold quality
renal medulla	UBERON:0000362	79.38	gold quality
omental fat pad	UBERON:0010414	79.06	gold quality
peritoneum	UBERON:0002358	78.96	gold quality
adipose tissue of abdominal region	UBERON:0007808	76.97	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	76.44	gold quality
parietal pleura	UBERON:0002400	74.85	gold quality
metanephros cortex	UBERON:0010533	73.18	gold quality
germinal epithelium of ovary	UBERON:0001304	72.66	gold quality
prefrontal cortex	UBERON:0000451	72.27	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	51.38
E-HCAD-10	yes	34.13
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

52 targeting DPYS, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 10)

• clinical, biochemical & genetic findings of two newly identified patients with a complete DHP deficiency; both patients were compound heterozygous for the missense mutation 1078T>C (W360R) in exon 6 and a novel missense mutation 1235G>T (R412M) in exon 7 (PMID:17383919)
• data presented in this study offers evidence for the possible genetic regulation of the DPYS gene and its possible influence on uracil catabolic pathway (PMID:18075467)
• Results indicate that missense and nonsense variants in DPYS are infrequent, however, the development of serious primarily gastrointestinal toxicity could be influenced by non-coding DPYS sequence variants c.-1T>C and IVS1-58T>C. (PMID:19649633)
• The p.S379R and p.L7V mutations were likely to cause structural destabilization and protein misfolding. Four mutations were identified in multiple unrelated DHP patients, indicating that DHP deficiency may be more common than anticipated. (PMID:20362666)
• Stepwise Cox regression modelling suggested that the methylation of genes HSPB1, CCND2 and DPYS contributed objective prognostic information to Gleason score and PSA with respect to prostate cancer-related death. (PMID:25193387)
• Two unrelated pediatric DPYS deficiency cases are being described as compound heterozygotes for a novel intronic mutation c.1443+5G>A in intron 8 and a previously described missense mutation c.1001A>G (p.Q334R) in exon 6. (PMID:26771602)
• 4 newly identified DHP deficient patients presented with strongly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in urine and a highly variable clinical presentation, ranging from asymptomatic to infantile spasm and reduced white matter and brain atrophy. Analysis of the DHP gene (DPYS) showed the presence of 8 variants including 4 novel/rare missense variants and one novel deletion. (PMID:29054612)
• This study defines dihydropyrimidines as potentially cytotoxic metabolites that may offer an opportunity for therapeutic-targeting of dihydropyrimidinase activity in solid tumors. (PMID:31853544)
• Functional Characterization of 12 Dihydropyrimidinase Allelic Variants in Japanese Individuals for the Prediction of 5-Fluorouracil Treatment-Related Toxicity. (PMID:36414408)
• The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity. (PMID:37946254)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	dpys	ENSDARG00000079543
mus_musculus	Dpys	ENSMUSG00000022304
rattus_norvegicus	Dpys	ENSRNOG00000004298
drosophila_melanogaster	CRMP	FBGN0023023
caenorhabditis_elegans	dhp-1	WBGENE00000963
caenorhabditis_elegans		WBGENE00000964

Paralogs (5): CRMP1 (ENSG00000072832), DPYSL2 (ENSG00000092964), DPYSL3 (ENSG00000113657), DPYSL4 (ENSG00000151640), DPYSL5 (ENSG00000157851)

Protein

Protein identifiers

Dihydropyrimidinase — Q14117 (reviewed: Q14117)

Alternative names: Dihydropyrimidine amidohydrolase, Hydantoinase

All UniProt accessions (3): Q14117, E5RG28, H0YEV7

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the second step of the reductive pyrimidine degradation, the reversible hydrolytic ring opening of dihydropyrimidines. Can catalyze the ring opening of 5,6-dihydrouracil to N-carbamyl-alanine and of 5,6-dihydrothymine to N-carbamyl-amino isobutyrate.

Subunit / interactions. Homotetramer.

Tissue specificity. Liver and kidney.

Post-translational modifications. Carboxylation allows a single lysine to coordinate two zinc ions.

Disease relevance. Dihydropyrimidinase deficiency (DPYSD) [MIM:222748] An autosomal recessive disorder of pyrimidine metabolism characterized by dihydropyrimidinuria. It is associated with a variable clinical phenotype characterized by epileptic or convulsive attacks, dysmorphic features and severe developmental delay, and congenital microvillous atrophy. Most patients are, however, asymptomatic. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 2 Zn(2+) ions per subunit.

Similarity. Belongs to the metallo-dependent hydrolases superfamily. Hydantoinase/dihydropyrimidinase family.

RefSeq proteins (1): NP_001376* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006680	Amidohydro-rel	Domain
IPR011059	Metal-dep_hydrolase_composite	Homologous_superfamily
IPR011778	Hydantoinase/dihydroPyrase	Family
IPR032466	Metal_Hydrolase	Homologous_superfamily
IPR050378	Metallo-dep_Hydrolases_sf	Family

Pfam: PF01979

Catalyzed reactions (Rhea), 1 shown:

• 5,6-dihydrouracil + H2O = 3-(carbamoylamino)propanoate + H(+) (RHEA:16121)

UniProt features (65 total): strand 19, helix 19, binding site 9, turn 8, sequence variant 5, modified residue 4, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2VR2	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14117-F1	96.00	0.94

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (9): 67; 69; 159 (via carbamate group); 159 (via carbamate group); 164; 192; 248; 326; 347

Post-translational modifications (4): 79, 159, 256, 510

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-73621	Pyrimidine catabolism

MSigDB gene sets: 221 (showing top): AAGCAAT_MIR137, MODULE_571, REACTOME_PYRIMIDINE_CATABOLISM, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_PYRIMIDINE_NUCLEOBASE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_PYRIMIDINE_CONTAINING_COMPOUND_CATABOLIC_PROCESS, GOBP_PYRIMIDINE_NUCLEOTIDE_METABOLIC_PROCESS, GOBP_PYRIMIDINE_NUCLEOTIDE_CATABOLIC_PROCESS, GOBP_NUCLEOBASE_METABOLIC_PROCESS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, HSIAO_LIVER_SPECIFIC_GENES

GO Biological Process (7): pyrimidine nucleobase catabolic process (GO:0006208), thymine catabolic process (GO:0006210), uracil catabolic process (GO:0006212), CMP catabolic process (GO:0006248), dCMP catabolic process (GO:0006249), UMP catabolic process (GO:0046050), dUMP catabolic process (GO:0046079)

GO Molecular Function (8): dihydropyrimidinase activity (GO:0004157), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), phosphoprotein binding (GO:0051219), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds (GO:0016810), metal ion binding (GO:0046872)

GO Cellular Component (3): cytosol (GO:0005829), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Nucleotide catabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
pyrimidine nucleobase catabolic process	2
pyrimidine ribonucleoside monophosphate catabolic process	2
pyrimidine ribonucleotide catabolic process	2
pyrimidine deoxyribonucleoside monophosphate catabolic process	2
pyrimidine deoxyribonucleotide catabolic process	2
protein binding	2
cellular anatomical structure	2
pyrimidine nucleobase metabolic process	1
nucleobase catabolic process	1
pyrimidine-containing compound catabolic process	1
thymine metabolic process	1
uracil metabolic process	1
CMP metabolic process	1
dCMP metabolic process	1
UMP metabolic process	1
dUMP metabolic process	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amides	1
transition metal ion binding	1
binding	1
catalytic activity	1
hydrolase activity	1
cation binding	1
cytoplasm	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1414 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DPYS	DPYD	Q12882	901
DPYS	UPB1	Q9UBR1	817
DPYS	UMPS	P11172	667
DPYS	TYMS	P04818	569
DPYS	RAB8A	P24407	490
DPYS	CAD	P27708	488
DPYS	GART	P22102	476
DPYS	UPP1	Q16831	475
DPYS	UPP2	O95045	463
DPYS	AGMAT	Q9BSE5	459
DPYS	AGXT2	Q9BYV1	454
DPYS	ATIC	P31939	447
DPYS	PDE4DIP	Q5VU43	440
DPYS	GLS2	Q9UI32	432
DPYS	MYO5B	Q9ULV0	430

IntAct

39 interactions, top by confidence:

A	B	Type	Score
DPYSL5	DPYSL4	psi-mi:“MI:0914”(association)	0.640
DPYSL3	DPYSL4	psi-mi:“MI:0914”(association)	0.640
DPYS	APPBP2	psi-mi:“MI:0915”(physical association)	0.560
CHAT	DPYS	psi-mi:“MI:0915”(physical association)	0.560
DPYS	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
GRIN2C	DPYS	psi-mi:“MI:0915”(physical association)	0.560
DPYS	GSN	psi-mi:“MI:0915”(physical association)	0.560
DPYS	HRAS	psi-mi:“MI:0915”(physical association)	0.560
DNALI1	DPYS	psi-mi:“MI:0915”(physical association)	0.560
BAG6	DPYS	psi-mi:“MI:0915”(physical association)	0.560
KLF11	DPYS	psi-mi:“MI:0915”(physical association)	0.560
NUP58	DPYS	psi-mi:“MI:0915”(physical association)	0.560
UBQLN1	DPYS	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (15): DPYS (Affinity Capture-MS), DPYS (Affinity Capture-MS), DPYSL3 (Affinity Capture-MS), DPYSL2 (Affinity Capture-MS), DPYSL5 (Affinity Capture-MS), DPYS (Two-hybrid), DPYS (Affinity Capture-MS), DPYSL5 (Affinity Capture-MS), DPYSL3 (Affinity Capture-MS), DPYSL2 (Affinity Capture-MS), DPYS (Affinity Capture-MS), DPYS (Affinity Capture-MS), DPYS (Affinity Capture-MS), DPYS (Affinity Capture-MS), DPYS (Affinity Capture-MS)

ESM2 similar proteins: A1A4L8, A2VDS1, A5GFY8, A5GFZ6, A6H791, A7MBC0, D4AAT7, E1BNQ4, E2QUI9, O14531, O35098, O43175, O75600, O95396, O95571, P13439, P31754, P38918, P43353, Q14117, Q16555, Q3T094, Q42942, Q4V831, Q4V9P6, Q5BJY6, Q5R7M2, Q5R824, Q5R9Y6, Q5RDK5, Q5U4Q9, Q5ZKP6, Q60HD7, Q62951, Q66IQ6, Q68FT9, Q6AY46, Q6P0U0, Q80XC2, Q8IW45

Diamond homologs: A1AF64, A7ZQY1, A7ZXG5, A8A415, B1ITC8, B1IZ89, B1XEG2, B6I0G2, B6I707, B7L7D8, B7LF59, B7LYD8, B7M4L5, B7MM60, B7MZ27, B7N7B8, B7N966, B7NW14, B7UHS3, C5A0E6, O02675, O08553, O13022, O14531, O35098, O69809, P47942, P81006, P97427, Q02C42, Q0TDX8, Q14117, Q14194, Q14195, Q16555, Q18677, Q1AS71, Q1J391, Q1R7F8, Q21773

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

238 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	9
Uncertain significance	127
Likely benign	42
Benign	15

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1360900	NM_001385.3(DPYS):c.568C>T (p.Gln190Ter)	Pathogenic
1395179	NM_001385.3(DPYS):c.56dup (p.Ser20fs)	Pathogenic
1419575	NM_001385.3(DPYS):c.151dup (p.Val51fs)	Pathogenic
1453274	NM_001385.3(DPYS):c.1217G>A (p.Trp406Ter)	Pathogenic
1453559	NM_001385.3(DPYS):c.1469dup (p.Ala491fs)	Pathogenic
184	NM_001385.3(DPYS):c.1001A>G (p.Gln334Arg)	Pathogenic
185	NM_001385.3(DPYS):c.1303G>A (p.Gly435Arg)	Pathogenic
187	NM_001385.3(DPYS):c.1235G>T (p.Arg412Met)	Pathogenic
2682641	NM_001385.3(DPYS):c.502T>C (p.Tyr168His)	Pathogenic
2737553	NM_001385.3(DPYS):c.1038_1039insT (p.Asn347Ter)	Pathogenic
2838625	NM_001385.3(DPYS):c.215dup (p.Phe74fs)	Pathogenic
3720857	NM_001385.3(DPYS):c.476del (p.Lys159fs)	Pathogenic
3902332	NM_001385.3(DPYS):c.904C>T (p.Arg302Ter)	Pathogenic
863103	NM_001385.3(DPYS):c.1393C>T (p.Arg465Ter)	Pathogenic
972740	NM_001385.3(DPYS):c.175G>T (p.Val59Phe)	Pathogenic
2424158	NC_000008.10:g.(?105436455)(105463652_?)dup	Likely pathogenic
2691719	NM_001385.3(DPYS):c.1064G>A (p.Arg355Gln)	Likely pathogenic
2691788	NM_001385.3(DPYS):c.983G>T (p.Cys328Phe)	Likely pathogenic
2735195	NM_001385.3(DPYS):c.1092+5del	Likely pathogenic
3899478	NM_001385.3(DPYS):c.794-1G>A	Likely pathogenic
3903245	NM_001385.3(DPYS):c.1443+2T>C	Likely pathogenic
4081351	NM_001385.3(DPYS):c.14C>A (p.Ser5Ter)	Likely pathogenic
4763156	NM_001385.3(DPYS):c.951-2A>G	Likely pathogenic
631543	NM_001385.3(DPYS):c.905G>A (p.Arg302Gln)	Likely pathogenic

SpliceAI

3093 predictions. Top by Δscore:

Variant	Effect	Δscore
8:104392777:CACT:C	donor_loss	1.0000
8:104392778:ACTC:A	donor_loss	1.0000
8:104392779:CT:C	donor_loss	1.0000
8:104392780:TCAC:T	donor_loss	1.0000
8:104392781:CA:C	donor_loss	1.0000
8:104392782:AC:A	donor_gain	1.0000
8:104392783:CC:C	donor_gain	1.0000
8:104392987:TAGTC:T	acceptor_gain	1.0000
8:104392992:C:CC	acceptor_gain	1.0000
8:104392998:T:C	acceptor_gain	1.0000
8:104392998:T:TC	acceptor_gain	1.0000
8:104393000:G:C	acceptor_gain	1.0000
8:104393000:G:GC	acceptor_gain	1.0000
8:104424385:CTATG:C	acceptor_gain	1.0000
8:104428122:C:CC	acceptor_gain	1.0000
8:104429543:A:AC	donor_gain	1.0000
8:104429544:C:CC	donor_gain	1.0000
8:104429547:A:AC	donor_gain	1.0000
8:104429548:G:C	donor_gain	1.0000
8:104444277:G:C	donor_gain	1.0000
8:104447320:GTAC:G	donor_loss	1.0000
8:104447321:TACCT:T	donor_loss	1.0000
8:104447322:ACCT:A	donor_loss	1.0000
8:104447323:CCT:C	donor_gain	1.0000
8:104447500:TAAC:T	acceptor_gain	1.0000
8:104447502:AC:A	acceptor_gain	1.0000
8:104447502:ACCT:A	acceptor_loss	1.0000
8:104447503:CC:C	acceptor_gain	1.0000
8:104447504:C:CC	acceptor_gain	1.0000
8:104466653:GTAC:G	donor_loss	1.0000

AlphaMissense

3408 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:104424345:G:C	S379R	0.999
8:104424345:G:T	S379R	0.999
8:104424347:T:G	S379R	0.999
8:104428008:C:G	R355P	0.999
8:104427994:A:G	W360R	0.998
8:104427994:A:T	W360R	0.998
8:104428029:C:T	G348E	0.998
8:104428030:C:A	G348W	0.998
8:104428095:T:A	D326V	0.998
8:104428102:C:A	G324W	0.998
8:104392949:G:C	N426K	0.997
8:104392949:G:T	N426K	0.997
8:104424266:A:G	W406R	0.997
8:104424266:A:T	W406R	0.997
8:104424334:G:T	A383D	0.997
8:104428046:A:C	F342L	0.997
8:104428046:A:T	F342L	0.997
8:104428048:A:G	F342L	0.997
8:104428082:G:C	F330L	0.997
8:104428082:G:T	F330L	0.997
8:104428084:A:G	F330L	0.997
8:104428088:G:C	C328W	0.997
8:104428113:A:G	L320P	0.997
8:104466716:G:C	H69D	0.997
8:104466728:C:G	D65H	0.997
8:104424305:C:G	G393R	0.996
8:104424305:C:T	G393R	0.996
8:104424306:T:A	K392N	0.996
8:104424306:T:G	K392N	0.996
8:104428098:G:A	T325I	0.996

dbSNP variants (sampled 300 via entrez): RS1000001246 (8:104423468 T>A,C), RS1000110343 (8:104418468 T>C), RS1000128650 (8:104410640 C>T), RS1000133040 (8:104454551 G>C), RS1000135912 (8:104390487 A>C), RS1000166891 (8:104390927 C>T), RS1000168669 (8:104455216 G>A), RS1000172979 (8:104460236 T>C,G), RS1000278645 (8:104405684 T>C,G), RS1000372293 (8:104398169 G>C), RS1000375409 (8:104449029 A>G), RS1000453964 (8:104399377 C>T), RS1000478114 (8:104442538 C>A,T), RS1000509588 (8:104436020 G>C), RS1000544326 (8:104412015 C>T)

Disease associations

OMIM: gene MIM:613326 | disease phenotypes: MIM:222748

GenCC curated gene-disease

Disease	Classification	Inheritance
dihydropyrimidinuria	Strong	Autosomal recessive

Mondo (1): dihydropyrimidinuria (MONDO:0009111)

Orphanet (1): Dihydropyrimidinuria (Orphanet:38874)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000280	Coarse facial features
HP:0000717	Autism
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001262	Excessive daytime somnolence
HP:0001357	Plagiocephaly
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001762	Talipes equinovarus
HP:0001942	Metabolic acidosis
HP:0002013	Vomiting
HP:0002020	Gastroesophageal reflux
HP:0002023	Anal atresia
HP:0002062	Abnormal pyramidal tract morphology
HP:0002376	Developmental regression
HP:0002500	Abnormal cerebral white matter morphology
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003654	Reduced dihydropyrimidine dehydrogenase level
HP:0003710	Exercise-induced muscle cramps
HP:0007018	Attention deficit hyperactivity disorder
HP:0007256	Abnormal pyramidal sign
HP:0007308	Extrapyramidal dyskinesia
HP:0009803	Short phalanx of finger

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006941_32	Irritable mood	4.000000e-08
GCST009849_1	Hallux valgus	5.000000e-07
GCST009885_4	Salivary metabolite levels	8.000000e-54
GCST012488_41	L1-L4 bone mineral density x serum urate levels interaction	3.000000e-06
GCST90007003_6	Gut microbiota relative abundance (Ruminococcus belonging to family Lachnospiraceae)	8.000000e-07

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0009594	irritability measurement
EFO:0010637	salivary metabolite measurement
EFO:0010641	3-ureidopropionate measurement
EFO:0004531	urate measurement
EFO:0007701	spine bone mineral density
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2465 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs143004875	Toxicity	3	capecitabine;fluorouracil	Drug Toxicity
rs2669429	Toxicity	3	atenolol	Hyperglycemia;Hypertension

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2669429	DPYS	3	3.00	1	atenolol
rs2959023	DPYS		0.00	0
rs121964923	DPYS		0.00	0
rs201280871	DPYS		0.00	0
rs770063251	DPYS		0.00	0
rs143004875	DPYS	3	2.50	1	capecitabine;fluorouracil

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
Aflatoxin B1	affects expression, decreases expression	3
sodium arsenite	affects methylation, decreases expression	2
Valproic Acid	decreases expression	2
methyleugenol	decreases expression	1
bisphenol A	increases methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
bisphenol S	decreases methylation	1
Rosiglitazone	decreases expression	1
Troglitazone	decreases expression	1
Acetaminophen	decreases expression	1
Diazinon	decreases methylation	1
Hydrogen Peroxide	affects expression	1
Lipopolysaccharides	increases expression, affects cotreatment	1
Sulindac	increases expression	1
Testosterone	decreases expression	1
Tobacco Smoke Pollution	increases methylation	1
Urethane	decreases expression	1
Cyclosporine	decreases expression	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.