CYP2R1

Summary

CYP2R1 (cytochrome P450 family 2 subfamily R member 1, HGNC:20580) is a protein-coding gene on chromosome 11p15.2, encoding Vitamin D 25-hydroxylase (Q6VVX0). A cytochrome P450 monooxygenase involved in activation of vitamin D precursors.

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This enzyme is a microsomal vitamin D hydroxylase that converts vitamin D into the active ligand for the vitamin D receptor. A mutation in this gene has been associated with selective 25-hydroxyvitamin D deficiency.

Source: NCBI Gene 120227 — RefSeq curated summary.

At a glance

• Gene–disease (curated): vitamin D hydroxylation-deficient rickets, type 1B (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 13
• Clinical variants (ClinVar): 255 total — 13 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 60
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_024514

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20580
Approved symbol	CYP2R1
Name	cytochrome P450 family 2 subfamily R member 1
Location	11p15.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000186104
Ensembl biotype	protein_coding
OMIM	608713
Entrez	120227

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 4 protein_coding, 4 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined

ENST00000334636, ENST00000525015, ENST00000526276, ENST00000526489, ENST00000529043, ENST00000530609, ENST00000532378, ENST00000532641, ENST00000532805, ENST00000534686, ENST00000921519, ENST00000921520

RefSeq mRNA: 17 — MANE Select: NM_024514 NM_001377214, NM_001377215, NM_001377216, NM_001377217, NM_001377227, NM_001400558, NM_001400559, NM_001400560, NM_001400561, NM_001400562, NM_001400563, NM_001400564, NM_001400565, NM_001400566, NM_001400567, NM_001400568, NM_024514

CCDS: CCDS7818, CCDS91446

Canonical transcript exons

ENST00000334636 — 5 exons

Exon	Start	End
ENSE00001334140	14891981	14892231
ENSE00002168235	14877440	14878297
ENSE00003514450	14880136	14880768
ENSE00003655780	14879114	14879443
ENSE00003667487	14885776	14885917

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 97.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.6932 / max 62.7453, expressed in 1615 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118760	4.1926	1504
118761	1.4865	796
118759	0.0096	3
206196	0.0045	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	97.47	gold quality
male germ cell	CL:0000015	93.34	gold quality
left testis	UBERON:0004533	92.97	gold quality
right testis	UBERON:0004534	92.92	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.93	gold quality
testis	UBERON:0000473	91.30	gold quality
lower esophagus mucosa	UBERON:0035834	91.12	gold quality
body of pancreas	UBERON:0001150	90.70	gold quality
skin of abdomen	UBERON:0001416	90.10	gold quality
skin of leg	UBERON:0001511	89.93	gold quality
mucosa of transverse colon	UBERON:0004991	89.85	gold quality
body of stomach	UBERON:0001161	89.58	gold quality
rectum	UBERON:0001052	89.29	gold quality
esophagus mucosa	UBERON:0002469	89.04	gold quality
descending thoracic aorta	UBERON:0002345	88.93	gold quality
granulocyte	CL:0000094	88.69	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.55	gold quality
thoracic aorta	UBERON:0001515	88.47	gold quality
ascending aorta	UBERON:0001496	88.44	gold quality
minor salivary gland	UBERON:0001830	88.36	gold quality
zone of skin	UBERON:0000014	88.01	gold quality
transverse colon	UBERON:0001157	87.74	gold quality
mouth mucosa	UBERON:0003729	87.69	gold quality
gingival epithelium	UBERON:0001949	87.55	gold quality
upper leg skin	UBERON:0004262	87.49	gold quality
jejunal mucosa	UBERON:0000399	87.37	gold quality
tibia	UBERON:0000979	87.28	gold quality
esophagus	UBERON:0001043	87.16	gold quality
cortical plate	UBERON:0005343	87.04	gold quality
stomach	UBERON:0000945	86.97	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.83

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting CYP2R1, 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-8485	100.00	77.57	4731
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-3164	99.02	68.39	1071
HSA-MIR-6820-3P	99.02	68.50	1035
HSA-MIR-3127-5P	97.52	65.24	786
HSA-MIR-12128	96.67	66.98	1471

Literature-anchored findings (GeneRIF, showing 40)

• CYP2R1 is a strong candidate for the microsomal vitamin D 25-hydroxylase. (PMID:12867411)
• Results suggest that CYP2R1 plays a physiologically important role in the vitamin D 25-hydroxylation in humans. (PMID:15465040)
• CYP27B1 gene could play a functional role in the pathogenesis of type 1 diabetes through modulation of its mRNA expression and influence serum levels of 1,25(OH)(2)D(3) via the -1260 C/A polymorphism (PMID:17223345)
• Novel association of CYP2R1 polymorphisms in patients with type 1 diabetes and with circulating levels of vitamin D. (PMID:17607662)
• The structure reveals the secosteroid binding mode in an extended active site and allows rationalization of the molecular basis of the inherited rickets associated with CYP2R1. (PMID:18511070)
• No significant differences were observed in genotype or allele frequencies between case and control groups for VDR, CYP27B1 or CYP2R1 SNPs (PMID:19783860)
• Studies indicate that vitamin D synthesis, a two-step process, starts with a 25-hydroxylation primarily by CYP2R1 and a subsequent 1alpha-hydroxylation via CYP27B1. (PMID:20619365)
• The results suggest that the CYP2R1 and GC genes may contribute to the variation of serum 25(OH)D levels in healthy populations. (PMID:20809279)
• We found a lower gene and protein expression of CYP2R1 in samples with hypospermatogenesis and Sertoli-cell-only syndrome. (PMID:21270327)
• Study confirms that variation in CYP2R1 is associated with predisposition to autoimmune disease type 1 diabetes. (PMID:21441443)
• Our study is the first to confirm the association of variants in DHCR7 and CYP2R1 with 25(OH)-vitamin D levels in patients with chronic liver diseases. (PMID:22576297)
• genetic association study in population in Singapore: Data suggest that diet and SNPs in CYP2R1, CYP3A4 (cytochrome P450, subfamily 3A, polypeptide 4), and GC/VDBP (group-specific component) interact to contribute to vitamin D deficiency. (PMID:22583563)
• Our study found that variant genotypes of single nucleotide polymorphisms in the CYP2R1 gene, rs10766197, rs12794714, rs10741657, rs2060793 and rs1562902, were all significantly associated with plasma 25-hydroxyvitamin D levels. (PMID:22801813)
• CYP2R1 is a major vitamin D 25-hydroxylase that plays a fundamental role in activation of this essential vitamin. (PMID:22855339)
• In vitro and in vivo studies revealed that CYP2R1 expression in Leydig cells appeared to be hCG dependent. (PMID:23047203)
• Finding suggest that GG genotype of CYP2R1 polymorphism and/or CC genotype of CYP27B1 polymorphism increased the risk of developing of type 1 diabetes in Egyptian children. (PMID:23063903)
• genetic association studies in postmenopausal Caucasian women in US: Data suggest that 4 SNPs in CYP2R1 are associated with 25-hydroxyvitamin D in blood (i.e., vitamin D deficiency); vitamin D intake/seasonal sunlight exposure modify these effects. (PMID:23190755)
• Genetic variation in CYP2R1 associated with lower serum 25(OH)D has a decreased risk of aggressive prostate cancer. (PMID:23377224)
• Data indicate that the same nucleotide polymorphisms (SNPs) genotypes of CYP2R1, GC and DHCR7 that are associated with reduced 25(OH)D3 serum levels were found to be associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). (PMID:23734184)
• CYP2R1 rs10741657 A>G polymorphism is associated with colon cancer recurrence. (PMID:23793229)
• SNPs in the CYP24A1, CYP2R1, calcium sensing receptor (CASR), vitamin D binding protein (GC), retinoid X receptor-alpha (RXRA) and megalin (LRP2) genes were significantly associated with pancreas cancer risk. (PMID:23826131)
• The GAA haplotype of the CYP2R1 gene (P = 0.026) is associated with susceptibility to rickets. (PMID:24073854)
• Low baseline DNA methylation levels in the promoter region of CYP2R1 is associated with low vitamin D response. (PMID:24128439)
• Results show that upregulated gene expression of CYP2R1 may lead to misbalance of vitamin D metabolites and may contribute to the pathogenesis of RCC (PMID:24245571)
• Data indicate that 1,25(OH)2D3 treatment time-dependently increased Cytochrome P450 2R1 (CYP2R1) expression in oral squamous cell carcinomas. (PMID:24497297)
• common polymorphisms in GC and CYP2R1 are associated with serum 25(OH)D concentrations in the Caucasian population and that certain haplotypes may predispose to lower 25(OH)D concentrations in late summer in Denmark. (PMID:24587115)
• Studied whether abnormal endometrial expression of CYP27A1 and/or CYP2R1 may impair VDR-antiproliferative properties in endometrial carcinoma. (PMID:24732451)
• In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7) (PMID:24974252)
• The CYP2R1 rs10741657 polymorphism is a novel genetic marker for coronary artery disease. (PMID:25003556)
• genetic differences in the VDR gene may be involved in the development of AITD and the activity of GD, whereas the genetic differences in the GC and CYP2R1 genes may be involved with the intractability of GD. (PMID:25046415)
• The increase in [25(OH)D] attributable to vitamin D3 supplementation may vary according to common genetic differences in vitamin D 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1), and the vitamin D receptor (VDR) genes. (PMID:25070320)
• CYP2R1 variants had no significant association with serum 25-OHD3 levels among postmenopausal women of the Han ethnic group in Beijing. (PMID:25079458)
• Data indicate that genome-wide significant associations were found both at age 6 and 14 with single nucleotide polymorphisms (SNPs) on chromosome 11p15 in phosphodiesterase 3B, cGMP-inhibited protein PDE3B/cytochrome P-450 CYP2R1 genes. (PMID:25208829)
• Significant associations were found between the GC (rs2282679 and rs7041), CYP2R1 (rs10741657) single nucleotide polymorphisms and the active form of Vitamin D, 25(OH)D. (PMID:25405862)
• genetic association studies in populations in Denmark: Data suggest that an SNP in CYP2R1 (rs10741657) is associated with response to either UVB treatment or vitamin D3 fortification of bread and milk in prevention of vitamin D deficiency in winter. (PMID:25527766)
• Found a significant upregulation of the CYP2R1 gene in human brain pericytes challenged with tumor necrosis factor-alpha and interferon-gamma. Results suggest the existence of an autocrine/paracrine vitamin D system in the neurovascular unit. (PMID:25730676)
• The 25-hydroxylases CYP2R1 and CYP27A1 catalyze vitamin D to its circulating form 25-hydroxyvitamin D. (PMID:25845986)
• CYP2R1 alleles have dosage-dependent effects on vitamin D homeostasis. CYP2R1 mutations cause a novel form of genetic vitamin D deficiency with semidominant inheritance. (PMID:25942481)
• Allelic variations in CYP2R1 and GC affect vitamin D levels, but variant alleles on VDR and DHCR7 were not correlated with vitamin D deficiency. (PMID:26038244)
• A significant association was found between decreased ASD risk and child CYP2R1 AA-genotype. (PMID:26073892)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cyp2r1	ENSDARG00000056587
mus_musculus	Cyp2r1	ENSMUSG00000030670
rattus_norvegicus	Cyp2r1	ENSRNOG00000011367

Paralogs (15): CYP2W1 (ENSG00000073067), CYP2D6 (ENSG00000100197), CYP2C18 (ENSG00000108242), CYP2E1 (ENSG00000130649), CYP2J2 (ENSG00000134716), CYP2C9 (ENSG00000138109), CYP2C8 (ENSG00000138115), CYP2U1 (ENSG00000155016), CYP2C19 (ENSG00000165841), CYP2S1 (ENSG00000167600), CYP2B6 (ENSG00000197408), CYP2F1 (ENSG00000197446), CYP2A13 (ENSG00000197838), CYP2A7 (ENSG00000198077), CYP2A6 (ENSG00000255974)

Protein

Protein identifiers

Vitamin D 25-hydroxylase — Q6VVX0 (reviewed: Q6VVX0)

Alternative names: Cytochrome P450 2R1

All UniProt accessions (4): E9PJT9, E9PS56, Q6VVX0, K7EMQ4

UniProt curated annotations — full annotation on UniProt →

Function. A cytochrome P450 monooxygenase involved in activation of vitamin D precursors. Catalyzes hydroxylation at C-25 of both forms of vitamin D, vitamin D(2) and D(3) (calciol). Can metabolize vitamin D analogs/prodrugs 1alpha-hydroxyvitamin D(2) (doxercalciferol) and 1alpha-hydroxyvitamin D(3) (alfacalcidol) forming 25-hydroxy derivatives. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase).

Subunit / interactions. Homodimer.

Subcellular location. Endoplasmic reticulum membrane. Microsome membrane.

Disease relevance. Rickets vitamin D-dependent 1B (VDDR1B) [MIM:600081] An autosomal recessive disorder caused by a selective deficiency of the active form of vitamin D (1,25-dihydroxyvitamin D3) and resulting in defective bone mineralization and clinical features of rickets. The patients sera have low calcium concentrations, low phosphate concentrations, elevated alkaline phosphatase activity and low levels of 25-hydroxyvitamin D. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Hormone biosynthesis; vitamin D biosynthesis.

Similarity. Belongs to the cytochrome P450 family.

RefSeq proteins (17): NP_001364143, NP_001364144, NP_001364145, NP_001364146, NP_001364156, NP_001387487, NP_001387488, NP_001387489, NP_001387490, NP_001387491, NP_001387492, NP_001387493, NP_001387494, NP_001387495, NP_001387496, NP_001387497, NP_078790* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001128	Cyt_P450	Family
IPR002401	Cyt_P450_E_grp-I	Family
IPR017972	Cyt_P450_CS	Conserved_site
IPR036396	Cyt_P450_sf	Homologous_superfamily
IPR050182	Cytochrome_P450_fam2	Family

Pfam: PF00067

Enzyme classification (BRENDA):

• EC 1.14.14.24 — vitamin D 25-hydroxylase (BRENDA: 7 organisms, 34 substrates, 4 inhibitors, 22 Km, 14 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
1ALPHA-HYDROXYVITAMIN D3	0.0006–0.0113	6
VITAMIN D3	0.0008–0.032	6
1ALPHA-HYDROXYVITAMIN D2	0.0042–0.018	4
BUFURALOL	0.001–0.0014	2
VITAMIN D2	0.0004–0.002	2
1ALPHA-HYDROXYCHOLECALCIFEROL	0.054	1
25-HYDROXY-VITAMIN D3	0.0071	1

Catalyzed reactions (Rhea), 4 shown:

• calciol + reduced [NADPH–hemoprotein reductase] + O2 = calcidiol + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:32903)
• vitamin D2 + reduced [NADPH–hemoprotein reductase] + O2 = 25-hydroxyvitamin D2 + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:46580)
• 1alpha-hydroxyvitamin D2 + reduced [NADPH–hemoprotein reductase] + O2 = 1alpha,25-dihydroxyvitamin D2 + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:46584)
• alfacalcidol + reduced [NADPH–hemoprotein reductase] + O2 = calcitriol + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:49272)

UniProt features (43 total): helix 20, strand 11, turn 6, binding site 2, sequence variant 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3CZH	X-RAY DIFFRACTION	2.3
3DL9	X-RAY DIFFRACTION	2.72
3C6G	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6VVX0-F1	96.26	0.93

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 (2): 250; 448 (axial binding residue)

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-196791	Vitamin D (calciferol) metabolism
R-HSA-211916	Vitamins
R-HSA-5579027	Defective CYP27B1 causes VDDR1B

MSigDB gene sets: 277 (showing top): REACTOME_BIOLOGICAL_OXIDATIONS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_POLYOL_METABOLIC_PROCESS, BILD_HRAS_ONCOGENIC_SIGNATURE, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_VITAMIN_D_METABOLIC_PROCESS, GOBP_STEROID_BIOSYNTHETIC_PROCESS, GOBP_VITAMIN_BIOSYNTHETIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, TANAKA_METHYLATED_IN_ESOPHAGEAL_CARCINOMA, GOBP_LIPID_BIOSYNTHETIC_PROCESS, HAN_SATB1_TARGETS_DN, RODRIGUES_DCC_TARGETS_DN, RIGGI_EWING_SARCOMA_PROGENITOR_UP

GO Biological Process (10): obsolete organic acid metabolic process (GO:0006082), vitamin metabolic process (GO:0006766), xenobiotic metabolic process (GO:0006805), response to cesium ion (GO:0010164), response to ionizing radiation (GO:0010212), calcitriol biosynthetic process from calciol (GO:0036378), vitamin D metabolic process (GO:0042359), lipid metabolic process (GO:0006629), response to metal ion (GO:0010038), vitamin D biosynthetic process (GO:0042368)

GO Molecular Function (10): iron ion binding (GO:0005506), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen (GO:0016712), heme binding (GO:0020037), vitamin D 25-hydroxylase activity (GO:0030343), protein homodimerization activity (GO:0042803), D3 vitamins binding (GO:1902271), monooxygenase activity (GO:0004497), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705), metal ion binding (GO:0046872)

GO Cellular Component (4): cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of steroids	1
Cytochrome P450 - arranged by substrate type	1
Metabolic disorders of biological oxidation enzymes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oxidoreductase activity	2
cellular anatomical structure	2
small molecule metabolic process	1
metabolic process	1
cellular response to xenobiotic stimulus	1
response to metal ion	1
response to radiation	1
vitamin D biosynthetic process	1
polyol biosynthetic process	1
vitamin D3 metabolic process	1
steroid metabolic process	1
primary metabolic process	1
response to chemical	1
steroid biosynthetic process	1
vitamin D metabolic process	1
fat-soluble vitamin biosynthetic process	1
transition metal ion binding	1
monooxygenase activity	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	1
tetrapyrrole binding	1
steroid hydroxylase activity	1
calcitriol biosynthetic process from calciol	1
identical protein binding	1
protein dimerization activity	1
vitamin D binding	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1604 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYP2R1	GC	P02774	895
CYP2R1	DHCR7	Q9UBM7	886
CYP2R1	NADSYN1	Q6IA69	840
CYP2R1	AMDHD1	Q96NU7	736
CYP2R1	PTH	P01270	695
CYP2R1	CYP27A1	Q02318	635
CYP2R1	NR1I3	Q14994	628
CYP2R1	FGF23	Q9GZV9	614
CYP2R1	NR1I2	O75469	587
CYP2R1	FDXR	P22570	587
CYP2R1	PPIG	Q13427	584
CYP2R1	NDC80	O14777	581
CYP2R1	LRP2	P98164	576
CYP2R1	FDX1	P10109	573
CYP2R1	C10orf88	Q9H8K7	570

IntAct

0 interactions, top by confidence:

BioGRID (5): CYP2R1 (Affinity Capture-MS), CYP2R1 (Co-fractionation), CYP2R1 (Co-fractionation), CYP2R1 (Affinity Capture-RNA), CYP2R1 (Affinity Capture-RNA)

ESM2 similar proteins: A0A087X1C5, E9Q816, O18992, O46658, P00191, P03940, P08686, P10633, P10634, P10635, P11714, P12394, P12938, P12939, P15540, P24456, P24457, P30437, P51589, P51590, P52786, P70085, P78329, Q01361, Q0IIF9, Q29473, Q29488, Q2LA59, Q2LA60, Q2LCM1, Q2XNC8, Q2XNC9, Q4V8D1, Q64403, Q64562, Q64680, Q6GUQ4, Q6VVW9, Q6VVX0, Q7Z449

Diamond homologs: A0A087X1C5, E9Q5K4, F1Q8C3, O18809, O18992, O35293, O46658, O54749, O54750, O55071, O62671, O93297, P00176, P00178, P00179, P00180, P00181, P00182, P04167, P05178, P05179, P05180, P05181, P08682, P08683, P10610, P10632, P10633, P10634, P10635, P11371, P11712, P11714, P12789, P12790, P12791, P12938, P12939, P15123, P17666

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CYP2R1	“up-regulates quantity”	calcidiol	“chemical modification”
CYP2R1	“down-regulates quantity”	“vitamin D”	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	8
Uncertain significance	133
Likely benign	72
Benign	4

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1016554	NM_024514.5(CYP2R1):c.701G>A (p.Trp234Ter)	Pathogenic
1926241	NM_024514.5(CYP2R1):c.391C>T (p.Arg131Ter)	Pathogenic
2117407	NM_024514.5(CYP2R1):c.294C>A (p.Cys98Ter)	Pathogenic
2873273	NM_024514.5(CYP2R1):c.872del (p.Pro291fs)	Pathogenic
2897896	NM_024514.5(CYP2R1):c.733C>T (p.Gln245Ter)	Pathogenic
3022350	NM_024514.5(CYP2R1):c.1270C>T (p.Arg424Ter)	Pathogenic
3603688	NM_024514.5(CYP2R1):c.254C>G (p.Ser85Ter)	Pathogenic
3690028	NM_024514.5(CYP2R1):c.41_50del (p.Leu14fs)	Pathogenic
3711033	NM_024514.5(CYP2R1):c.88del (p.Leu30fs)	Pathogenic
4706311	NM_024514.5(CYP2R1):c.135del (p.Leu46fs)	Pathogenic
4717754	NM_024514.5(CYP2R1):c.121_122del (p.Pro41fs)	Pathogenic
4733603	NM_024514.5(CYP2R1):c.15G>A (p.Trp5Ter)	Pathogenic
977185	NM_024514.5(CYP2R1):c.768dup (p.Leu257fs)	Pathogenic
3599226	NM_024514.5(CYP2R1):c.1000+1G>A	Likely pathogenic
3599235	NM_024514.5(CYP2R1):c.726dup (p.His243fs)	Likely pathogenic
3599240	NM_024514.5(CYP2R1):c.563C>A (p.Ser188Ter)	Likely pathogenic
3599247	NM_024514.5(CYP2R1):c.416T>G (p.Leu139Ter)	Likely pathogenic
3599248	NM_024514.5(CYP2R1):c.412C>T (p.Arg138Ter)	Likely pathogenic
3599255	NM_024514.5(CYP2R1):c.226-1G>T	Likely pathogenic
369982	GRCh37/hg19 11p15.2(chr11:14504463-14909461)x1	Likely pathogenic
369983	GRCh37/hg19 11p15.2(chr11:14657389-14918308)x1	Likely pathogenic

SpliceAI

912 predictions. Top by Δscore:

Variant	Effect	Δscore
11:14885920:T:C	acceptor_gain	1.0000
11:14880764:TAAGC:T	acceptor_gain	0.9900
11:14880769:C:CC	acceptor_gain	0.9900
11:14880769:C:CG	acceptor_loss	0.9900
11:14880770:T:C	acceptor_loss	0.9900
11:14885777:T:TA	donor_gain	0.9900
11:14885778:C:A	donor_gain	0.9900
11:14885920:T:TC	acceptor_gain	0.9900
11:14887727:T:TA	donor_gain	0.9900
11:14890482:C:CT	acceptor_gain	0.9900
11:14879137:T:TA	donor_gain	0.9800
11:14879216:CAAAG:C	acceptor_gain	0.9800
11:14879222:G:C	acceptor_gain	0.9800
11:14879222:G:GC	acceptor_gain	0.9800
11:14880766:AGCCT:A	acceptor_gain	0.9800
11:14880767:GC:G	acceptor_gain	0.9800
11:14880767:GCCTG:G	acceptor_gain	0.9800
11:14880768:CC:C	acceptor_gain	0.9800
11:14885769:AACAT:A	donor_loss	0.9800
11:14885770:ACATA:A	donor_loss	0.9800
11:14885771:CATA:C	donor_loss	0.9800
11:14885772:ATACC:A	donor_loss	0.9800
11:14885773:T:TG	donor_loss	0.9800
11:14885774:ACCTC:A	donor_gain	0.9800
11:14885775:C:CT	donor_loss	0.9800
11:14885775:CCTCC:C	donor_gain	0.9800
11:14885919:T:C	acceptor_gain	0.9800
11:14880765:AAGCC:A	acceptor_gain	0.9700
11:14880768:CCTG:C	acceptor_gain	0.9700
11:14885774:ACCT:A	donor_gain	0.9600

AlphaMissense

3293 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:14879121:A:C	F441L	0.997
11:14879121:A:T	F441L	0.997
11:14879123:A:G	F441L	0.997
11:14879335:C:G	R370T	0.997
11:14885816:T:A	R109S	0.997
11:14885816:T:G	R109S	0.997
11:14879334:T:A	R370S	0.996
11:14879334:T:G	R370S	0.996
11:14879344:T:A	E367V	0.996
11:14879357:C:G	A363P	0.996
11:14885817:C:G	R109T	0.996
11:14885880:A:T	V88D	0.996
11:14879300:C:G	A382P	0.995
11:14880216:A:G	L307P	0.995
11:14878291:C:G	R446T	0.994
11:14879169:A:C	F425L	0.994
11:14879169:A:T	F425L	0.994
11:14879171:A:G	F425L	0.994
11:14879235:A:C	N403K	0.994
11:14879235:A:T	N403K	0.994
11:14879303:G:C	H381D	0.994
11:14880175:A:G	W321R	0.994
11:14880175:A:T	W321R	0.994
11:14880237:A:G	L300P	0.994
11:14878290:T:A	R446S	0.993
11:14878290:T:G	R446S	0.993
11:14885818:T:C	R109G	0.993
11:14878284:A:C	C448W	0.992
11:14879185:A:G	F420S	0.992
11:14879245:A:T	V400E	0.992

dbSNP variants (sampled 300 via entrez): RS1000039860 (11:14877013 C>G), RS1000329191 (11:14892237 A>C,G), RS1000383583 (11:14885548 A>C), RS1000661350 (11:14890967 G>A,C), RS1000712687 (11:14885890 A>G,T), RS1000818426 (11:14890796 C>T), RS1000934921 (11:14884480 A>C), RS1002674104 (11:14888425 C>T), RS1002722676 (11:14880982 G>C), RS1003595792 (11:14892581 G>A), RS1004400830 (11:14881390 G>A), RS1004506686 (11:14890240 T>C,G), RS1004711215 (11:14879217 A>T), RS1004858323 (11:14889966 A>C), RS1005240778 (11:14892638 G>C,T)

Disease associations

OMIM: gene MIM:608713 | disease phenotypes: MIM:600081

GenCC curated gene-disease

Disease	Classification	Inheritance
vitamin D hydroxylation-deficient rickets, type 1B	Strong	Autosomal recessive
vitamin D-dependent rickets, type 1	Supportive	Autosomal recessive

Mondo (4): vitamin D hydroxylation-deficient rickets, type 1B (MONDO:0010810), pulmonary disease, chronic obstructive, susceptibility to (MONDO:0100167), vitamin D-dependent rickets, type 1 (MONDO:0009924), thyroid hemiagenesis (MONDO:0019860)

Orphanet (2): Hypocalcemic vitamin D-dependent rickets (Orphanet:289157), Thyroid hemiagenesis (Orphanet:95719)

HPO phenotypes

60 total (30 of 60 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000684	Delayed eruption of teeth
HP:0000737	Irritability
HP:0000867	Secondary hyperparathyroidism
HP:0000886	Deformed rib cage
HP:0000893	Bulging of the costochondral junction
HP:0000897	Rachitic rosary
HP:0000920	Enlargement of the costochondral junction
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001281	Tetany
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001324	Muscle weakness
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001538	Protuberant abdomen
HP:0001638	Cardiomyopathy
HP:0001744	Splenomegaly
HP:0001931	Hypochromic anemia
HP:0001974	Increased total leukocyte count
HP:0002007	Frontal bossing
HP:0002148	Hypophosphatemia
HP:0002199	Hypocalcemic seizures
HP:0002240	Hepatomegaly
HP:0002653	Bone pain
HP:0002659	Increased susceptibility to fractures
HP:0002663	Delayed epiphyseal ossification
HP:0002748	Rickets
HP:0002749	Osteomalacia

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000664_3	Vitamin D levels	3.000000e-17
GCST000697_3	Vitamin D insufficiency	3.000000e-20
GCST002602_11	Vitamin D levels	2.000000e-10
GCST002602_9	Vitamin D levels	4.000000e-08
GCST004726_3	Vitamin D levels	2.000000e-90
GCST005366_3	Vitamin D levels (dietary vitamin D intake interaction)	2.000000e-38
GCST005367_5	Vitamin D levels	2.000000e-46
GCST005729_2	Serum 25-Hydroxyvitamin D levels	1.000000e-10
GCST005782_13	Serum 25-Hydroxyvitamin D levels	2.000000e-06
GCST008103_53	Bipolar disorder	4.000000e-07
GCST009671_2	Serum 25-Hydroxyvitamin D levels	4.000000e-11
GCST010171_3	Midgestational total 25-hydroxyvitamin D levels (maternal genetic effect)	2.000000e-06
GCST012014_2	Serum 25-Hydroxyvitamin D levels	3.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0003762	vitamin D deficiency
EFO:0008539	vitamin D dietary intake measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C562688	Vitamin D Hydroxylation-Deficient Rickets, Type 1A (supp.)
C564005	Vitamin D Hydroxylation-Deficient Rickets, Type 1B (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523986 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 15,540 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL477772	PAZOPANIB	4	15,540

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10741657	Efficacy	3	peginterferon alfa-2b;ribavirin	Chronic hepatitis C virus infection

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10741657	CYP2R1	3	3.00	1	peginterferon alfa-2b;ribavirin
rs12794714	CYP2R1		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — CYP2 family: physiological enzymes subset

ChEMBL bioactivities

16 potent at pChembl≥5 of 17 total, top 16 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.60	IC50	251.2	nM	CHEMBL601428
6.16	IC50	700	nM	CHEMBL3330409
6.05	IC50	900	nM	CHEMBL3330410
5.96	IC50	1100	nM	CHEMBL2130955
5.72	IC50	1900	nM	CHEMBL2130955
5.60	IC50	2500	nM	CHEMBL5612347
5.55	IC50	2800	nM	CHEMBL2130955
5.43	IC50	3700	nM	CHEMBL5406721
5.43	IC50	3700	nM	CHEMBL46909
5.42	IC50	3800	nM	CHEMBL5418617
5.41	IC50	3900	nM	CHEMBL5429178
5.31	IC50	4900	nM	CHEMBL2130955
5.23	IC50	5900	nM	CHEMBL5406218
5.22	IC50	6053	nM	CHEMBL65590
5.10	IC50	7900	nM	PAZOPANIB
5.00	IC50	1e+04	nM	CHEMBL5395150

PubChem BioAssay actives

18 with measured affinity, of 466 total; 15 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
8-imidazol-1-yl-5,6,7,8-tetrahydroquinoline	2022035: Inhibition of CYP450 (unknown origin)	ic50	0.0335	uM
N-(4-chlorophenyl)-5-ethyl-N-methyl-3-phenyl-1,2-oxazole-4-carboxamide	2108148: Inhibition of CYP450 (unknown origin)	ic50	0.2512	uM
2-(dimethylamino)-2-(2-ethylphenyl)-N-[3-(3-sulfamoylphenyl)-1H-indazol-5-yl]acetamide	2119433: Inhibition of CYP450 (unknown origin)	ic50	0.7000	uM
2-pyrrolidin-1-yl-N-[3-(3-sulfamoylphenyl)-1H-indazol-5-yl]-2-thiophen-3-ylacetamide	2119433: Inhibition of CYP450 (unknown origin)	ic50	0.9000	uM
2-[4-(trifluoromethyl)phenyl]chromen-4-one	1860369: Inhibition of CYP450 in human HCT-116 cells assessed as 20-HETE formation in presence of arachidonic acid incubated for 15 mins by multi-enzyme assay based LC-MS/MS analysis	ic50	1.1000	uM
4-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-4-N-[[(7R)-5,6,7,8-tetrahydro-1,6-naphthyridin-7-yl]methyl]cyclohexane-1,4-diamine	2124397: Inhibition of CYP450 (unknown origin)	ic50	2.5000	uM
1-[3-(2,4-dimethoxyphenyl)phenyl]-2,4-dimethoxybenzene	1973305: Inhibition of CYP450 in pooled human liver microsomes in presence of NADPH measured every 3 mins for 120 mins by fluorescence based analysis	ic50	3.7000	uM
1-[(E)-2-(2,4-dimethoxyphenyl)ethenyl]-3,5-dimethoxybenzene	1973305: Inhibition of CYP450 in pooled human liver microsomes in presence of NADPH measured every 3 mins for 120 mins by fluorescence based analysis	ic50	3.7000	uM
2,4-bis(3,5-dimethoxyphenyl)pyrimidine	1973305: Inhibition of CYP450 in pooled human liver microsomes in presence of NADPH measured every 3 mins for 120 mins by fluorescence based analysis	ic50	3.8000	uM
2,5-bis(3,5-dimethoxyphenyl)thiophene	1973305: Inhibition of CYP450 in pooled human liver microsomes in presence of NADPH measured every 3 mins for 120 mins by fluorescence based analysis	ic50	3.9000	uM
4-[2-(2,4-dimethoxyphenyl)-1,3-thiazol-4-yl]phenol	1973305: Inhibition of CYP450 in pooled human liver microsomes in presence of NADPH measured every 3 mins for 120 mins by fluorescence based analysis	ic50	5.9000	uM
1-pyridin-4-yl-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalen-4-ol	2022025: Inhibition of CYP450 in human liver microsomes	ic50	6.0534	uM
(5R)-3-[1-(1H-indol-2-ylmethyl)piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-1,3-oxazolidin-2-one	306257: Inhibition of CYP450	ic50	7.9433	uM
3-[1-[(3,4-dimethylphenyl)methyl]piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)-1,3-oxazolidin-2-one	306257: Inhibition of CYP450	ic50	10.0000	uM
1-[3-(3,5-dimethoxyphenyl)phenyl]-3,5-dimethoxybenzene	1973305: Inhibition of CYP450 in pooled human liver microsomes in presence of NADPH measured every 3 mins for 120 mins by fluorescence based analysis	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	5
Tobacco Smoke Pollution	decreases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
arsenite	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
tebuconazole	decreases expression	1
CGP 52608	affects binding, increases reaction	1
25-hydroxyvitamin D	affects abundance	1
obeticholic acid	increases expression	1
Grape Seed Proanthocyanidins	decreases expression, affects cotreatment	1
(+)-JQ1 compound	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Amiodarone	increases expression	1
Catechin	affects cotreatment, decreases expression	1
Coal	decreases expression, increases abundance	1
Copper	affects binding, increases expression	1
Coumestrol	affects cotreatment, increases expression	1
Disulfiram	affects binding, increases expression	1

ChEMBL screening assays

183 unique, capped per target: 181 admet, 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2060324	ADMET	Inhibition of CYP450	Rapid identification of ETP-46992, orally bioavailable PI3K inhibitor, selective versus mTOR. — Bioorg Med Chem Lett
CHEMBL4614611	Binding	Drug metabolism in human liver microsomes assessed as Cytochrome P450-mediated formation of 12-OHNVP by measuring Kcat/Km ratio in presence of NADPH regenerating reagents by uHPLC-MS/MS analysis	Twelfth-Position Deuteration of Nevirapine Reduces 12-Hydroxy-Nevirapine Formation and Nevirapine-Induced Hepatocyte Death. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06624657	Not specified	COMPLETED	High-intensity Interval Training and Vitamin D Effects on Bone Metabolism Among Women Diagnosed With Osteoporosis
NCT07275177	Not specified	COMPLETED	Effect of Vitamin D on Body Composition and Functionality of Older Adults
NCT07366450	Not specified	NOT_YET_RECRUITING	High-Dose vs Standard Ergocalciferol for Vitamin D Normalization in Aggressive Non-Hodgkin Lymphoma