CYP27B1
protein-codingcytochrome P450 family 27 subfamily B member 1, the group of Cytochrome P450 family 27
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. The protein encoded by this gene localizes to the inner mitochondrial membrane where it hydroxylates 25-hydroxyvitamin D3 at the 1alpha position. This reaction synthesizes 1alpha,25-dihydroxyvitamin D3, the active form of vitamin D3, which binds to the vitamin D receptor and regulates calcium metabolism. Thus this enzyme regulates the level of biologically active vitamin D and plays an important role in calcium homeostasis. Mutations in this gene can result in vitamin D-dependent rickets type I. [provided by RefSeq, Jul 2008]
- VDD1
- PDDR
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009924
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0020723
Submitter: ClinGen
CYP27B1 was first reported in relation to autosomal recessive vitamin D-dependent rickets in 1997 (Fu et al., PMID: 9415400). This condition is characterized by features including rickets, increased susceptibility to bone fractures, other skeletal features (such as enlargement of the wrists and ankles), hypocalcemia, hypophosphatemia, hypotonia, seizures, and aminoaciduria. 14 variants (missense, frameshift, splicing, nonsense) that have been reported in 10 probands in 6 publications (PMIDs: 9415400, 9486994, 12050193, 31261480, 35663328, 39452491) are included in this curation. More evidence is available in the literature (PMID: 39778955), but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (biochemical functional evidence, mouse models; PMIDs: 9295274, 30031146). Biochemical function evidence revealed that this gene is essential in calcium homeostasis. In a mouse model, knockout mice had skeletal anomalies, rickets, hypocalcemia, and growth delay. In summary, there is definitive evidence supporting the relationship between CYP27B1 and autosomal recessive vitamin D-dependent rickets. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Tublopathy GCEP on the meeting date 6/04/2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0020723
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Endocrine
Intervention: Endocrine
Rationale: Medical treatment with forms of vitamin D can be effective for prevention and treatment of manifestations, such as skeletal anomalies and seizures
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CYP27B1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000785.4. 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 | 174 | 1 | 178 | ||
| missense | 9 | 32 | 147 | 8 | 1 | 197 |
| nonsense | 12 | 3 | 15 | |||
| start loss | 1 | 1 | ||||
| frameshift | 33 | 12 | 45 | |||
| splice donor/acceptor (+/-2bp) | 4 | 8 | 12 | |||
| Total | 58 | 56 | 150 | 182 | 2 | 448 |
Highest pathogenic variant AF is 0.00020900044
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000776.1 | 9 | MANE Select | |
| Ensembl | ENSP00000228606.4 | 9 | MANE Select | |
| Ensembl | ENSP00000449472.2 | 4 | Standard | |
| Ensembl | ENSP00000520828.1 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cyp27b1 | Danio rerio | Structure: ventral wall of dorsal aorta Quality: has fewer parts of type abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Steroid biosynthesis - Homo sapiens (human)
- Tuberculosis - Homo sapiens (human)
- Vitamin D Metabolism
- Vitamin D Receptor Pathway
- Nuclear Receptors in Lipid Metabolism and Toxicity
Biological Process
- vitamin metabolic process
- calcium ion transport
- negative regulation of cell population proliferation
- negative regulation of calcidiol 1-monooxygenase activity
- positive regulation of vitamin D 24-hydroxylase activity
Molecular Function
- calcidiol 1-monooxygenase activity
- iron ion binding
- heme binding
Cellular Component
- cytoplasm
- mitochondrion
- mitochondrial outer membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000228606
- Coding exons
- 9
- Length
- 6653
- Individuals with no LoFs
- 125655
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 93
- Defined
- 125748
- p
- 0.000370
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0655 | 278 | 281 | 0.989 | 0.0000150 | 3190 |
| Missense (PolyPhen) | 105 | 118.45 | 0.88642 | 1388 | ||
| Synonymous | -1.67 | 144 | 121 | 1.19 | 0.00000623 | 1137 |
| Loss of Function | 1.62 | 14 | 22.3 | 0.629 | 9.95e-7 | 245 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00056 | 0.00043 | rare |
| Latino/Admixed American | 0.00069 | 0.00069 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00054 | 0.00054 | rare |
| Finnish | 0.00023 | 0.00023 | rare |
| European (Non-Finnish) | 0.00028 | 0.00028 | rare |
| South Asian | 0.00033 | 0.00033 | rare |
| Other | 0.00082 | 0.00081 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the conversion of 25-hydroxyvitamin D3 (25(OH)D3) to 1-alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)(2)D3), and of 24,25-dihydroxyvitamin D3 (24,25(OH)(2)D3) to 1- alpha,24,25-trihydroxyvitamin D3 (1alpha,24,25(OH)(3)D3). Is also active with 25-hydroxy-24-oxo-vitamin D3. Plays an important role in normal bone growth, calcium metabolism, and tissue differentiation. {ECO:0000269|PubMed:10518789}.;
Recessive Scores
- pRec
- 0.399
Intolerance Scores
- LoFtool
- 0.456
- RVIS EVS
- -0.4
- RVIS percentile EVS
- 26.53
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.286
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |