CYP2R1

protein-coding

cytochrome P450 family 2 subfamily R member 1, the group of Cytochrome P450 family 2

Gene summary

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. [provided by RefSeq, Jul 2008]

MANE transcript

NM_024514.5

Inheritance

ClinVar variants

P:30U:146B:60

Top phenotype

Vitamin D hydroxylation deficient rickets, type 1B

gnomAD constraint

pLI —, LoF o/e 0.79

Max pathogenic AF

—

Genomic locus

chr11:14,877,440-14,892,231

External References & Databases

Ensembl (ENSG00000186104)

Transcript & Mutation Effects

hg38 • Region Span ~14.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

vitamin D-dependent rickets, type 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009924

Submitter: Orphanet

vitamin D hydroxylation-deficient rickets, type 1BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010810

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Vitamin D hydroxylation deficient rickets, type 1BAR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: Medical treatment (eg, with supraphysiological levels of vitamin D3 or D2) has been reported to result in improvement or resolution of biochemical and clinical/radiographic anomalies

Refs: 8201479; 15128933; 22855339

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYP2R1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 177

Vitamin D hydroxylation-deficient rickets, type 1BTotal: 101

not specifiedTotal: 62

CYP2R1-related disorderTotal: 8

CYP2R1-related disordersTotal: 2

Decreased circulating calcitriol concentrationTotal: 1

Hypophosphataemia or ricketsTotal: 1

Vitamin D-dependent rickets, type 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024514.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	55 clinvar		58
missense		1 clinvar	139 clinvar	5 clinvar		145
nonsense	6 clinvar	9 clinvar	2 clinvar			17
start loss			1 clinvar			1
frameshift	6 clinvar	5 clinvar				11
splice donor/acceptor (+/-2bp)		3 clinvar	1 clinvar			4
Total	12	18	146	60	0	236

Highest pathogenic variant AF is 0.0001927248

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024514.5	RefSeq	NP_078790.2	5	MANE Select
ENST00000334636.10	Ensembl	ENSP00000334592.5	5	MANE Select
NM_001377214.1	RefSeq	NP_001364143.1	4	Standard
NM_001377215.1	RefSeq	NP_001364144.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cyp2r1	Danio rerio	Structure: subcutaneous fat Quality: increased amount abnormal

Gene / Model

Organism

Observed Phenotype

cyp2r1

Danio rerio

Structure: subcutaneous fat

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Steroid biosynthesis - Homo sapiens (human)
Vitamin D Metabolism
Oxidation by Cytochrome P450
Metapathway biotransformation Phase I and II
Phase I - Functionalization of compounds

Biological Process

organic acid metabolic process
vitamin metabolic process
xenobiotic metabolic process
response to cesium ion
response to ionizing radiation

Molecular Function

iron ion binding
steroid hydroxylase activity
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
heme binding
vitamin D3 25-hydroxylase activity

Cellular Component

cytoplasm
endoplasmic reticulum membrane
organelle membrane
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000334636
Coding exons: 5
Length: 14246
Individuals with no LoFs: 125604
Homozygous LoFs: 0
Heterozygous LoFs: 144
Defined: 125748
p: 0.000573

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.481	247	269	0.918	0.0000129	3284
Missense (PolyPhen)		83	116.68	0.71134		1441
Synonymous	-0.468	106	100	1.06	0.00000466	969
Loss of Function	0.899	17	21.5	0.791	0.00000134	249

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00052	0.00049	rare
Latino/Admixed American	0.0018	0.0017	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00061	0.00060	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00045	0.00042	rare
South Asian	0.00040	0.00039	rare
Other	0.00067	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Has a D-25-hydroxylase activity on both forms of vitamin D, vitamin D(2) and D(3). {ECO:0000269|PubMed:12867411, ECO:0000269|PubMed:15465040, ECO:0000269|PubMed:18511070}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:15128933, ECO:0000269|PubMed:25942481}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.189

Intolerance Scores

LoFtool: 0.669
RVIS EVS: -0.09
RVIS percentile EVS: 46.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.186

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium