CYP27B1

Chr 12AR

cytochrome P450 family 27 subfamily B member 1

Also known as: CP2B, CYP1, CYP1alpha, CYP27B, P450c1, PDDR, VDD1, VDDR

NCBI Gene: 1594 ENSG00000111012 UniProt: O15528 OMIM: 609506

The protein is a cytochrome P450 monooxygenase that catalyzes the rate-limiting step in vitamin D activation by converting 25-hydroxyvitamin D3 to the hormonally active form 1α,25-dihydroxyvitamin D3, which regulates calcium and phosphorus homeostasis through the vitamin D receptor. Mutations cause vitamin D-dependent rickets type I with autosomal recessive inheritance, affecting bone mineralization and calcium metabolism. The gene shows very low constraint against loss-of-function variants (pLI near zero), consistent with recessive disease requiring biallelic mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.981 OMIM phenotype

Clinical Summary— CYP27B1

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Gene-Disease Validity (ClinGen)

vitamin D-dependent rickets, type 1A · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.98LOEUF

pLI 0.000

Z-score 1.62

OE 0.63 (0.41–0.98)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.07Z-score

OE missense 0.99 (0.90–1.09)

278 obs / 281.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.63 (0.41–0.98)

0≤0.351.4

Missense OE?0.99 (0.90–1.09)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 14 / 22.3Missense obs/exp: 278 / 281.1Syn Z: -1.67

This gene — mechanism propensity

0.7132th %ile

GOF

0.7127th %ile

LOF

0.2873th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.