QDPR

Summary

QDPR (quinoid dihydropteridine reductase, HGNC:9752) is a protein-coding gene on chromosome 4p15.32, encoding Dihydropteridine reductase (P09417). Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin.

This gene encodes the enzyme dihydropteridine reductase, which catalyzes the NADH-mediated reduction of quinonoid dihydrobiopterin. This enzyme is an essential component of the pterin-dependent aromatic amino acid hydroxylating systems. Mutations in this gene resulting in QDPR deficiency include aberrant splicing, amino acid substitutions, insertions, or premature terminations. Dihydropteridine reductase deficiency presents as atypical phenylketonuria due to insufficient production of biopterin, a cofactor for phenylalanine hydroxylase.

Source: NCBI Gene 5860 — RefSeq curated summary.

At a glance

• Gene–disease (curated): dihydropteridine reductase deficiency (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 380 total — 32 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000320

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9752
Approved symbol	QDPR
Name	quinoid dihydropteridine reductase
Location	4p15.32
Locus type	gene with protein product
Status	Approved
Aliases	DHPR, PKU2, SDR33C1
Ensembl gene	ENSG00000151552
Ensembl biotype	protein_coding
OMIM	612676
Entrez	5860

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 12 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000281243, ENST00000428702, ENST00000501943, ENST00000505710, ENST00000507439, ENST00000508623, ENST00000511609, ENST00000513615, ENST00000514300, ENST00000706645, ENST00000910936, ENST00000910937, ENST00000910938, ENST00000910939, ENST00000910940, ENST00000910941, ENST00000943484

RefSeq mRNA: 2 — MANE Select: NM_000320 NM_000320, NM_001306140

CCDS: CCDS3421, CCDS77904

Canonical transcript exons

ENST00000281243 — 7 exons

Exon	Start	End
ENSE00001133162	17492232	17492340
ENSE00001693584	17511950	17512090
ENSE00003490939	17486395	17487236
ENSE00003504757	17504379	17504475
ENSE00003583070	17509271	17509363
ENSE00003608918	17490662	17490745
ENSE00003672898	17501719	17501859

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 99.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.0670 / max 1592.2292, expressed in 1806 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51528	20.5419	1799
51527	6.2937	1426
51529	4.4770	426
51530	0.7425	116
51526	0.0118	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
inferior vagus X ganglion	UBERON:0005363	99.88	gold quality
lateral globus pallidus	UBERON:0002476	99.85	gold quality
superior vestibular nucleus	UBERON:0007227	99.80	gold quality
substantia nigra pars compacta	UBERON:0001965	99.78	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.78	gold quality
inferior olivary complex	UBERON:0002127	99.75	gold quality
medulla oblongata	UBERON:0001896	99.74	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.71	gold quality
ventral tegmental area	UBERON:0002691	99.71	gold quality
subthalamic nucleus	UBERON:0001906	99.69	gold quality
pons	UBERON:0000988	99.67	gold quality
globus pallidus	UBERON:0001875	99.66	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.65	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.65	gold quality
midbrain	UBERON:0001891	99.62	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.62	gold quality
substantia nigra	UBERON:0002038	99.60	gold quality
spinal cord	UBERON:0002240	99.60	gold quality
medial globus pallidus	UBERON:0002477	99.60	gold quality
postcentral gyrus	UBERON:0002581	99.54	gold quality
putamen	UBERON:0001874	99.52	gold quality
parietal lobe	UBERON:0001872	99.47	gold quality
hypothalamus	UBERON:0001898	99.46	gold quality
cranial nerve II	UBERON:0000941	99.44	gold quality
CA1 field of hippocampus	UBERON:0003881	99.38	gold quality
endothelial cell	CL:0000115	99.35	gold quality
amygdala	UBERON:0001876	99.34	gold quality
Ammon’s horn	UBERON:0001954	99.33	gold quality
caudate nucleus	UBERON:0001873	99.25	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.17	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	5473.01
E-HCAD-25	yes	2533.49
E-MTAB-9435	yes	2171.36
E-MTAB-5061	yes	27.89
E-GEOD-81547	yes	25.52
E-HCAD-31	yes	23.39
E-GEOD-83139	yes	9.20
E-ENAD-27	yes	8.21
E-GEOD-125970	yes	6.62
E-MTAB-6379	no	351.30
E-MTAB-8894	no	141.40
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FEV, MYC

miRNA regulators (miRDB)

28 targeting QDPR, 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-3065-5P	99.97	71.56	3281
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-2682-5P	99.73	67.38	1055
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-4999-5P	99.35	69.15	926
HSA-MIR-140-3P	99.04	67.69	1324
HSA-MIR-581	98.39	67.42	835
HSA-MIR-4704-3P	98.28	69.33	1300
HSA-MIR-561-5P	98.25	68.13	1365
HSA-MIR-4717-5P	98.19	67.97	894
HSA-MIR-4457	98.09	67.12	1274
HSA-MIR-4329	97.68	66.26	1003
HSA-MIR-6760-3P	96.35	68.31	1001
HSA-MIR-576-3P	96.14	65.63	773
HSA-MIR-4798-3P	95.89	63.63	104

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 12)

• less than 30 microM H2O2 increase DHPR activities, whereas levels greater than 30 microM H2O2 deactivate the enzyme based on the oxidation of Met146 and Met151 in the sequence, consequently leading to disruption of the NADH-dependent enzyme active site. (PMID:15009710)
• Report suggests that serum prolactin levels can be a good biomarker for optimal dosage of hydroxylated precursors in long-term treatment monitoring for DHPR-deficient patients. (PMID:18425437)
• This protein has been found differentially expressed in the Wernicke’s Area from patients with schizophrenia. (PMID:19405953)
• This protein has been found differentially expressed in thalami from patients with schizophrenia. (PMID:20471030)
• the electrostatic regulatory interaction between the SPRY2 F loop residues (that bind to imperatoxin A) and the ASI/basic residues of RyR1 does not influence bi-directional DHPR-RyR1 signaling during skeletal EC coupling (PMID:21239886)
• JP1 and JP2 can facilitate the assembly of DHPR with other proteins of the excitation-contraction coupling machinery (PMID:22020936)
• The mutation spectrum of the QDPR gene is different in the Chinese population. Most mutations are related to severe phenotype. (PMID:25124972)
• The allele frequencies for the QDPR c.68G > A(0.3%) polymorphism is not a major cause of Parkinson’s disease in the Maltese. (PMID:27613114)
• Mutation of dihydropteridine reductase (QDPR) inhibited the regulation of TOR serine-threonine kinases (mTOR), suggesting that QDPR is a positive regulator of autophagy via suppressing mTOR signaling. (PMID:28633336)
• show for the first time statistically significant up regulation of iNOS in QDPR overexpressing astrocytes. Increased expression of iNOS associated with astrocyte pathology seen in many neurodegenerative disorders may have implications in autoimmune neurodegenerative disorders. (PMID:29355631)
• Comprehensive bioinformatics analysis of structural and functional consequences of deleterious missense mutations in the human QDPR gene. (PMID:37382215)
• QDPR deficiency drives immune suppression in pancreatic cancer. (PMID:38642552)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	qdprb.1	ENSDARG00000037378
danio_rerio	qdpra	ENSDARG00000040190
danio_rerio	qdprb.2	ENSDARG00000086859
danio_rerio	qdprb.3	ENSDARG00000090118
danio_rerio	qdprb.4	ENSDARG00000090822
mus_musculus	Qdpr	ENSMUSG00000015806
rattus_norvegicus	Qdpr	ENSRNOG00000003253
drosophila_melanogaster	Dhpr	FBGN0035964
caenorhabditis_elegans		WBGENE00011398

Protein

Protein identifiers

Dihydropteridine reductase — P09417 (reviewed: P09417)

Alternative names: HDHPR, Quinoid dihydropteridine reductase, Short chain dehydrogenase/reductase family 33C member 1

All UniProt accessions (6): P09417, A0A140VKA9, B7Z415, D6RGG7, D6RHJ7, H0Y8F7

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin.

Subunit / interactions. Homodimer.

Disease relevance. Hyperphenylalaninemia, BH4-deficient, C (HPABH4C) [MIM:261630] Rare autosomal recessive disorder characterized by hyperphenylalaninemia and severe neurologic symptoms (malignant hyperphenylalaninemia) including axial hypotonia and truncal hypertonia, abnormal thermogenesis, and microcephaly. These signs are attributable to depletion of the neurotransmitters dopamine and serotonin, whose syntheses are controlled by tryptophan and tyrosine hydroxylases that use BH-4 as cofactor. Patients do not respond to phenylalanine-restricted diet. HPABH4C is lethal if untreated. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the short-chain dehydrogenases/reductases (SDR) family.

Isoforms (2)

UniProt ID	Names	Canonical?
P09417-1	1	yes
P09417-2	2

RefSeq proteins (2): NP_000311, NP_001293069 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002347	SDR_fam	Family
IPR020904	Sc_DH/Rdtase_CS	Conserved_site
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily

Pfam: PF00106

Enzyme classification (BRENDA):

• EC 1.5.1.34 — 6,7-dihydropteridine reductase (BRENDA: 18 organisms, 80 substrates, 150 inhibitors, 186 Km, 65 kcat entries)

Substrate kinetics (BRENDA)

44 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
NADH	0.0008–2.9	58
QUINONOID DIHYDROBIOPTERIN	0.0003–1	24
NADPH	0.0014–0.77	21
QUINONOID 6-METHYL-7,8-DIHYDROPTERIN	0.0049–0.48	13
TETRAHYDROBIOPTERIN	0.0009–0.017	7
QUINONOID 6,7-DIMETHYL-7,8-DIHYDROPTERIDINE	0.008–0.46	6
QUINONOID-7,8-DIHYDROBIOPTERIN	0.0009–0.252	5
6-METHYL-TETRAHYDROPTERIN	0.0014–0.013	4
QUINONOID 7,8-(6H)-DIHYDROBIOPTERIN	0.0008–0.0063	4
QUINONOID 7,8-DIHYDRO-6-METHYLPTERIN	0.0014–0.013	4
QUINONOID 7,8-DIHYDROPTERIN	0.0009–0.144	4
QUINONOID 7,8-DIHYDROBIOPTERIN	0.0001–0.0016	3
5,6,7,8-TETRAHYDROBIOPTERIN	0.017–0.16	2
6,7-DIMETHYL-5,6,7,8-TETRAHYDROBIOPTERIN	0.0063–0.0152	2
6,7-DIMETHYL-5,6,7,8-TETRAHYDROPTERIN	0.012–0.015	2

Catalyzed reactions (Rhea), 2 shown:

• 5,6,7,8-tetrahydropteridine + NADP(+) = 6,7-dihydropteridine + NADPH + H(+) (RHEA:17865)
• 5,6,7,8-tetrahydropteridine + NAD(+) = 6,7-dihydropteridine + NADH + H(+) (RHEA:17869)

UniProt features (48 total): sequence variant 19, helix 9, strand 8, modified residue 5, turn 2, initiator methionine 1, chain 1, active site 1, binding site 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9DTW	X-RAY DIFFRACTION	1.39
1HDR	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P09417-F1	96.43	0.96

Functional residue map

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

Catalytic / active sites (1): 150 (proton acceptor)

Ligand- & substrate-binding residues (1): 14–38

Post-translational modifications (5): 2, 73, 79, 96, 102

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8964208	Phenylalanine metabolism

MSigDB gene sets: 234 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, MODULE_93, LIANG_HEMATOPOIESIS_STEM_CELL_NUMBER_SMALL_VS_HUGE_UP, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_POLYOL_METABOLIC_PROCESS, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, MODULE_66, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, BOYAULT_LIVER_CANCER_SUBCLASS_G12_DN, GOBP_PTERIDINE_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, JOHANSSON_BRAIN_CANCER_EARLY_VS_LATE_DN, ONKEN_UVEAL_MELANOMA_UP

GO Biological Process (5): amino acid metabolic process (GO:0006520), L-phenylalanine catabolic process (GO:0006559), tetrahydrobiopterin biosynthetic process (GO:0006729), dihydrobiopterin metabolic process (GO:0051066), pteridine-containing compound metabolic process (GO:0042558)

GO Molecular Function (5): 6,7-dihydropteridine reductase activity (GO:0004155), electron transfer activity (GO:0009055), NADPH binding (GO:0070402), NADH binding (GO:0070404), oxidoreductase activity (GO:0016491)

GO Cellular Component (4): cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Phenylalanine and tyrosine metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anion binding	2
cellular anatomical structure	2
cytoplasm	2
primary metabolic process	1
aromatic amino acid catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
diol biosynthetic process	1
pteridine-containing compound biosynthetic process	1
tetrahydrobiopterin metabolic process	1
pteridine-containing compound metabolic process	1
metabolic process	1
oxidoreductase activity, acting on the CH-NH group of donors, NAD or NADP as acceptor	1
molecular_function	1
NADP binding	1
NAD binding	1
catalytic activity	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
extracellular vesicle	1

Protein interactions and networks

STRING

3659 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
QDPR	RYR1	P21817	986
QDPR	PCBD1	P61457	945
QDPR	SPR	P35270	865
QDPR	GCH1	P30793	864
QDPR	PAH	P00439	845
QDPR	SLC46A1	Q96NT5	819
QDPR	DHFR2	Q86XF0	803
QDPR	PTS	Q03393	781
QDPR	DHFR	P00374	774
QDPR	DDC	P20711	721
QDPR	RYR2	Q92736	696
QDPR	GCHFR	P30047	668
QDPR	TH	P07101	637
QDPR	TPH1	P17752	603
QDPR	MAOB	P27338	579

IntAct

28 interactions, top by confidence:

A	B	Type	Score
PAGR1	KDM6A	psi-mi:“MI:0914”(association)	0.730
QDPR		psi-mi:“MI:0915”(physical association)	0.560
	QDPR	psi-mi:“MI:0915”(physical association)	0.560
ELF5	QDPR	psi-mi:“MI:0915”(physical association)	0.400
QDPR	QDPR	psi-mi:“MI:0915”(physical association)	0.370
QDPR	RXFP4	psi-mi:“MI:0915”(physical association)	0.370
CASP8	QDPR	psi-mi:“MI:0915”(physical association)	0.370
KRAS	QDPR	psi-mi:“MI:0915”(physical association)	0.370
APOA1	CNMD	psi-mi:“MI:0914”(association)	0.350
CAND1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
CUL1	LGALS8	psi-mi:“MI:0914”(association)	0.350
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
ENG	IGKV2-28	psi-mi:“MI:0914”(association)	0.350
ZDHHC5	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
IQCB1	PCP4L1	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
MAPRE1	SCAMP1	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
FECH	POTEF	psi-mi:“MI:0914”(association)	0.350
	QDPR	psi-mi:“MI:0914”(association)	0.350
SMNDC1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270
	QDPR	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (45): QDPR (Two-hybrid), ANKRD13A (Two-hybrid), HSPE1 (Co-fractionation), PDCD6 (Co-fractionation), QDPR (Co-fractionation), QDPR (Co-fractionation), QDPR (Co-fractionation), QDPR (Co-fractionation), QDPR (Co-fractionation), QDPR (Co-fractionation), QDPR (Co-fractionation), QDPR (Co-fractionation), QDPR (Co-fractionation), QDPR (Co-fractionation), QDPR (Co-fractionation)

ESM2 similar proteins: A0PJE2, A6QP05, A8DZE7, D2WKD9, F1QWW8, O75911, O77769, O88736, O88876, P09417, P11172, P11348, P13439, P13653, P15904, P20132, P23591, P24815, P56937, Q06136, Q0IH28, Q0VCN1, Q0VFE7, Q2KIJ5, Q3T0R4, Q3T0Z7, Q41578, Q42850, Q566S6, Q5PPL3, Q5R514, Q5R6U1, Q5R824, Q5RBE5, Q5RJY4, Q5ZID0, Q60555, Q62904, Q6GV12, Q6IAN0

Diamond homologs: P09417, P11348, Q3T0Z7, Q86A17, Q8BVI4, Q8MJ30

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	32
Likely pathogenic	16
Uncertain significance	107
Likely benign	149
Benign	48

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1067174	NM_000320.3(QDPR):c.508G>A (p.Gly170Ser)	Pathogenic
1335970	NM_000320.3(QDPR):c.447del (p.Tyr150fs)	Pathogenic
1335971	NM_000320.3(QDPR):c.545+1G>A	Pathogenic
1360342	NM_000320.3(QDPR):c.198+1G>A	Pathogenic
1453021	NM_000320.3(QDPR):c.644G>A (p.Trp215Ter)	Pathogenic
1458840	NM_000320.3(QDPR):c.614T>G (p.Leu205Ter)	Pathogenic
1459007	NC_000004.11:g.(?17488754)(17513677_?)del	Pathogenic
1679198	NM_000320.3(QDPR):c.488G>A (p.Ser163Asn)	Pathogenic
1679200	NM_000320.3(QDPR):c.383_407del (p.Glu128fs)	Pathogenic
2128493	NM_000320.3(QDPR):c.196C>T (p.Gln66Ter)	Pathogenic
2422871	NC_000004.11:g.(?17510874)(17513677_?)del	Pathogenic
2752602	NM_000320.3(QDPR):c.523del (p.Ala175fs)	Pathogenic
2757447	NM_000320.3(QDPR):c.576del (p.Lys192fs)	Pathogenic
2807160	NM_000320.3(QDPR):c.629+2T>C	Pathogenic
2910183	NM_000320.3(QDPR):c.328C>T (p.Gln110Ter)	Pathogenic
3068244	NM_000320.3(QDPR):c.344C>G (p.Ser115Trp)	Pathogenic
3384689	NM_000320.3(QDPR):c.73C>T (p.Arg25Ter)	Pathogenic
3647445	NC_000004.12:g.17490746del	Pathogenic
3695096	NM_000320.3(QDPR):c.629+1G>A	Pathogenic
3720573	NM_000320.3(QDPR):c.436+2552A>G	Pathogenic
4293433	NM_000320.3(QDPR):c.436+1G>C	Pathogenic
4747395	NM_000320.3(QDPR):c.673G>A (p.Gly225Arg)	Pathogenic
489	NM_000320.3(QDPR):c.366_368dup (p.Thr123dup)	Pathogenic
491	NM_000320.3(QDPR):c.322T>G (p.Trp108Gly)	Pathogenic
492	NM_000320.3(QDPR):c.106T>C (p.Trp36Arg)	Pathogenic
493	NM_000320.3(QDPR):c.437-429A>G	Pathogenic
494	NM_000320.3(QDPR):c.449A>G (p.Tyr150Cys)	Pathogenic
495	NM_000320.3(QDPR):c.270G>A (p.Trp90Ter)	Pathogenic
567509	NM_000320.3(QDPR):c.48C>G (p.Tyr16Ter)	Pathogenic
802058	NM_000320.3(QDPR):c.661C>T (p.Arg221Ter)	Pathogenic

SpliceAI

1418 predictions. Top by Δscore:

Variant	Effect	Δscore
4:17490660:A:AC	donor_gain	1.0000
4:17490661:C:CC	donor_gain	1.0000
4:17490661:CT:C	donor_gain	1.0000
4:17490661:CTCAA:C	donor_gain	1.0000
4:17490744:CC:C	acceptor_gain	1.0000
4:17490745:CC:C	acceptor_gain	1.0000
4:17492230:A:AC	donor_gain	1.0000
4:17492231:C:CC	donor_gain	1.0000
4:17492338:TACCT:T	acceptor_loss	1.0000
4:17492339:ACCTG:A	acceptor_loss	1.0000
4:17492340:CCT:C	acceptor_loss	1.0000
4:17492341:CTGGG:C	acceptor_loss	1.0000
4:17492342:T:G	acceptor_loss	1.0000
4:17501713:GCTTA:G	donor_loss	1.0000
4:17501714:CTTAC:C	donor_loss	1.0000
4:17501715:TTA:T	donor_loss	1.0000
4:17501716:TAC:T	donor_loss	1.0000
4:17501717:A:AC	donor_gain	1.0000
4:17501717:A:C	donor_loss	1.0000
4:17501718:C:CC	donor_gain	1.0000
4:17501855:GAGAG:G	acceptor_gain	1.0000
4:17501856:AGAG:A	acceptor_gain	1.0000
4:17504378:CA:C	donor_gain	1.0000
4:17509360:CCCA:C	acceptor_gain	1.0000
4:17509361:CCAC:C	acceptor_gain	1.0000
4:17490660:ACT:A	donor_gain	0.9900
4:17490661:CTC:C	donor_gain	0.9900
4:17490661:CTCA:C	donor_gain	0.9900
4:17490665:A:C	donor_gain	0.9900
4:17492225:CACT:C	donor_loss	0.9900

AlphaMissense

1582 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:17504406:A:G	W90R	0.998
4:17504406:A:T	W90R	0.998
4:17504404:C:A	W90C	0.997
4:17504404:C:G	W90C	0.997
4:17512005:C:T	G17D	0.997
4:17490687:A:G	W202R	0.996
4:17490687:A:T	W202R	0.996
4:17492315:C:A	K154N	0.996
4:17492315:C:G	K154N	0.996
4:17492329:A:G	Y150H	0.996
4:17501822:G:C	S111R	0.996
4:17501822:G:T	S111R	0.996
4:17501824:T:G	S111R	0.996
4:17511987:C:T	G23D	0.996
4:17490718:C:A	R191S	0.995
4:17490718:C:G	R191S	0.995
4:17490721:G:C	N190K	0.995
4:17490721:G:T	N190K	0.995
4:17492235:A:G	L181P	0.995
4:17492288:G:C	S163R	0.995
4:17492288:G:T	S163R	0.995
4:17492290:T:G	S163R	0.995
4:17501798:G:C	S119R	0.995
4:17501798:G:T	S119R	0.995
4:17501800:T:G	S119R	0.995
4:17504419:G:C	C85W	0.994
4:17504421:A:G	C85R	0.994
4:17504430:C:G	A82P	0.994
4:17511988:C:A	G23C	0.994
4:17511988:C:G	G23R	0.994

dbSNP variants (sampled 300 via entrez): RS1000017101 (4:17491175 T>A,C), RS10000532 (4:17497132 T>C), RS1000130838 (4:17513869 C>G), RS1000192766 (4:17493857 C>T), RS1000234079 (4:17509889 A>C,G), RS1000270112 (4:17509622 G>T), RS10004095 (4:17504818 A>C,T), RS1000434867 (4:17497368 T>G), RS1000545803 (4:17498216 C>A,T), RS1000578370 (4:17497814 T>C), RS10006709 (4:17504934 T>A,C), RS1000715019 (4:17486424 T>C), RS10008024 (4:17500607 A>G,T), RS1000826003 (4:17492494 A>C,T), RS10008333 (4:17497185 G>A)

Disease associations

OMIM: gene MIM:612676 | disease phenotypes: MIM:261630, MIM:261640

GenCC curated gene-disease

Disease	Classification	Inheritance
dihydropteridine reductase deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
dihydropteridine reductase deficiency	Definitive	AR

Mondo (3): dihydropteridine reductase deficiency (MONDO:0009862), hyperphenylalaninemia due to tetrahydrobiopterin deficiency (MONDO:0016543), BH4-deficient hyperphenylalaninemia A (MONDO:0009863)

Orphanet (3): Dihydropteridine reductase deficiency (Orphanet:226), Hyperphenylalaninemia due to tetrahydrobiopterin deficiency (Orphanet:238583), 6-pyruvoyl-tetrahydropterin synthase deficiency (Orphanet:13)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000737	Irritability
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001276	Hypertonia
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001954	Recurrent fever
HP:0002015	Dysphagia
HP:0002344	Progressive neurologic deterioration
HP:0002514	Cerebral calcification
HP:0003593	Infantile onset
HP:0003781	Excessive salivation
HP:0003828	Variable expressivity
HP:0004923	Hyperphenylalaninemia
HP:6000966	Diminished tissue dihydropteridine reductase activity

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_693	Blood protein levels	2.000000e-23

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535325	6-pyruvoyl-tetrahydropterin synthase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3730 (SINGLE PROTEIN)

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

ChEMBL bioactivities

13 potent at pChembl≥5 of 19 total, top 13 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.55	IC50	280	nM	CHEMBL324880
6.42	IC50	380	nM	CHEMBL110377
6.20	IC50	630	nM	CHEMBL109090
5.85	IC50	1400	nM	CHEMBL323998
5.55	Ki	2800	nM	CHEMBL108967
5.52	IC50	3000	nM	CHEMBL108967
5.47	IC50	3400	nM	CHEMBL323998
5.44	IC50	3600	nM	CHEMBL105897
5.30	IC50	5000	nM	CHEMBL110621
5.28	IC50	5200	nM	CHEMBL108679
5.23	IC50	5900	nM	CHEMBL108787
5.14	IC50	7200	nM	CHEMBL108496
5.03	IC50	9300	nM	CHEMBL322323

PubChem BioAssay actives

13 with measured affinity, of 31 total; 11 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-[4-(3,4-dihydroxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethanone	56917: Inhibitory activity against human liver Dihydrodipicolinate reductase (DHPR)	ic50	0.2800	uM
4-pyridin-4-ylbenzene-1,2-diol	56917: Inhibitory activity against human liver Dihydrodipicolinate reductase (DHPR)	ic50	0.3800	uM
4-(1-methylpyridin-1-ium-4-yl)benzene-1,2-diol bromide	56917: Inhibitory activity against human liver Dihydrodipicolinate reductase (DHPR)	ic50	0.6300	uM
4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,2-diol	56919: Inhibitory activity against human liver Dihydropteridine reductase using 10 uM qBH2 and 50 uM NADH assays	ic50	1.4000	uM
4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)phenol	53773: Noncompetitive Iinhibitory activity against human liver DHPR enzyme	ki	2.8000	uM
4-(1,2,3,6-tetrahydropyridin-4-yl)benzene-1,2-diol	56917: Inhibitory activity against human liver Dihydrodipicolinate reductase (DHPR)	ic50	3.6000	uM
1-[4-(4-hydroxy-3-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethanone	56917: Inhibitory activity against human liver Dihydrodipicolinate reductase (DHPR)	ic50	5.0000	uM
1-[4-(3,4-dihydroxyphenyl)piperidin-1-yl]ethanone	56917: Inhibitory activity against human liver Dihydrodipicolinate reductase (DHPR)	ic50	5.2000	uM
4-(1,2,3,6-tetrahydropyridin-4-yl)phenol	56917: Inhibitory activity against human liver Dihydrodipicolinate reductase (DHPR)	ic50	5.9000	uM
2-methoxy-4-(1,2,3,6-tetrahydropyridin-4-yl)phenol	56917: Inhibitory activity against human liver Dihydrodipicolinate reductase (DHPR)	ic50	7.2000	uM
2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)phenol	56917: Inhibitory activity against human liver Dihydrodipicolinate reductase (DHPR)	ic50	9.3000	uM

CTD chemical–gene interactions

49 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression, affects expression	5
bisphenol A	affects expression, decreases expression, increases expression	3
Cadmium	increases abundance, increases expression	2
Plant Extracts	affects cotreatment, increases expression, decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
decabromobiphenyl ether	increases expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Benztropine	decreases expression	1
Cisplatin	increases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652205	Binding	Binding affinity to human QDPR incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1QB	Abcam K-562 QDPR KO	Cancer cell line	Female
CVCL_D2LX	Abcam Raji QDPR KO	Cancer cell line	Male
CVCL_LG73	CG1254	Transformed cell line	Male
CVCL_WQ45	Abcam Jurkat QDPR KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT03519711	PHASE1/PHASE2	COMPLETED	A Study of PTC923 (CNSA-001) in Primary Tetrahydrobiopterin (BH4) Deficient Participants With Hyperphenylalaninemia
NCT01541397	Not specified	TERMINATED	Bone Mineral Density in Adults With Hyperphenylalaninemia on Kuvan Therapy
NCT01619722	Not specified	COMPLETED	Study of a National Cohort of Adult Patients With Phenylketonuria
NCT01869972	Not specified	COMPLETED	Biological Variation of Phenylalanine in Patients With Hyperphenylalaninemia
NCT02212288	Not specified	COMPLETED	Antioxidant Signature in Adult Patients With Phenylketonuria
NCT04896281	Not specified	RECRUITING	Phenylalanine-free Diet for Patients With Secondary Hyperphenylalaninemia in ICU