vitamin D hydroxylation-deficient rickets, type 1B

Summary

vitamin D hydroxylation-deficient rickets, type 1B (MONDO:0010810) is a disease caused by CYP2R1 (GenCC Strong), with 2 cohort genes and 3 clinical trials. Top therapeutic interventions include cholecalciferol.

At a glance

• Causal gene: CYP2R1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 102
• Clinical trials: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	vitamin D hydroxylation-deficient rickets, type 1B
Mondo ID	MONDO:0010810
MeSH	C564005
OMIM	600081
DOID	DOID:0080887
NCIT	C131074
UMLS	C1838657
MedGen	374020
GARD	0018415
Is cancer (heuristic)	no

Also known as: CYP2R1 vitamin D-dependent rickets, type 1 · rickets due to defect in vitamin D 25-hydroxylation deficiency · VDDR1B · Vitam D hydroxylation-deficient rickets type 1b · vitamin D 25-Hydroxylase deficiency · vitamin D hydroxylation-deficient rickets type 1b · vitamin D hydroxylation-deficient rickets, type 1B · vitamin D-dependent rickets, type 1 caused by mutation in CYP2R1

Data availability: 102 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › vitamin D hydroxylation-deficient rickets, type 1B

Related subtypes (28): cortisone reductase deficiency, familial hyperlipidemia, hypolipoproteinemia, steroid inherited metabolic disorder, corticosterone methyloxidase type 1 deficiency, lipoid proteinosis, 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency, mitochondrial trifunctional protein deficiency, pancreatic triacylglycerol lipase deficiency, glucocorticoid resistance, syndromic dyslipidemia, inborn disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation, disorder of plasmalogens biosynthesis, disorder of phospholipids, sphingolipids and fatty acids biosynthesis, inborn disorder of ketolysis, lysosomal lipid storage disorder, sterol metabolism disorder, disorder of sphingolipid biosynthesis, glycosylphosphatidylinositol biosynthesis defect 18, neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 55, inherited fatty acid metabolism disorder, glycosylphosphatidylinositol biosynthesis defect 16, glycosylphosphatidylinositol biosynthesis defect 15, glycosylphosphatidylinositol biosynthesis defect 17, CYP7B1-related disorder of oxysterol accumulation

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

102 retrieved; paginated sample, class counts are floors:

74 uncertain significance, 9 pathogenic/likely pathogenic, 6 likely pathogenic, 5 benign/likely benign, 4 likely benign, 2 conflicting classifications of pathogenicity, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029900	NM_024514.5(CYP2R1):c.1120dup (p.Ile374fs)	CYP2R1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332743	NM_024514.5(CYP2R1):c.595C>T (p.Arg199Ter)	CYP2R1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1450676	NM_024514.5(CYP2R1):c.433C>T (p.Arg145Ter)	CYP2R1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1929675	NM_024514.5(CYP2R1):c.628_629del (p.Met210fs)	CYP2R1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1950218	NM_024514.5(CYP2R1):c.289G>T (p.Glu97Ter)	CYP2R1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2134	NM_024514.5(CYP2R1):c.296T>C (p.Leu99Pro)	CYP2R1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2993511	NM_024514.5(CYP2R1):c.219C>A (p.Tyr73Ter)	CYP2R1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3599265	NM_024514.5(CYP2R1):c.31_40dup (p.Leu14fs)	CYP2R1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
977184	NM_024514.5(CYP2R1):c.367+1G>A	CYP2R1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
977185	NM_024514.5(CYP2R1):c.768dup (p.Leu257fs)	CYP2R1	Pathogenic	criteria provided, multiple submitters, no conflicts
977186	NM_024514.5(CYP2R1):c.124_137delinsCG (p.Gly42_Leu46delinsArg)	PDE3B	Pathogenic	no assertion criteria provided
3599226	NM_024514.5(CYP2R1):c.1000+1G>A	CYP2R1	Likely pathogenic	criteria provided, single submitter
3599235	NM_024514.5(CYP2R1):c.726dup (p.His243fs)	CYP2R1	Likely pathogenic	criteria provided, single submitter
3599240	NM_024514.5(CYP2R1):c.563C>A (p.Ser188Ter)	CYP2R1	Likely pathogenic	criteria provided, single submitter
3599247	NM_024514.5(CYP2R1):c.416T>G (p.Leu139Ter)	CYP2R1	Likely pathogenic	criteria provided, single submitter
3599248	NM_024514.5(CYP2R1):c.412C>T (p.Arg138Ter)	CYP2R1	Likely pathogenic	criteria provided, single submitter
3599255	NM_024514.5(CYP2R1):c.226-1G>T	CYP2R1	Likely pathogenic	criteria provided, single submitter
2374820	NM_024514.5(CYP2R1):c.497A>G (p.Asn166Ser)	CYP2R1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3499227	NM_024514.5(CYP2R1):c.505A>G (p.Ile169Val)	CYP2R1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1000400	NM_024514.5(CYP2R1):c.352A>G (p.Met118Val)	CYP2R1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1008903	NM_024514.5(CYP2R1):c.1166T>A (p.Val389Glu)	CYP2R1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1310664	NM_024514.5(CYP2R1):c.577C>A (p.Leu193Met)	CYP2R1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1345679	NM_024514.5(CYP2R1):c.253T>C (p.Ser85Pro)	CYP2R1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1385510	NM_024514.5(CYP2R1):c.1363C>T (p.Arg455Trp)	CYP2R1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1391635	NM_024514.5(CYP2R1):c.1364G>A (p.Arg455Gln)	CYP2R1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1939745	NM_024514.5(CYP2R1):c.112G>A (p.Gly38Ser)	CYP2R1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2016123	NM_024514.5(CYP2R1):c.1498A>T (p.Arg500Ter)	CYP2R1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2067369	NM_024514.5(CYP2R1):c.661G>A (p.Ala221Thr)	CYP2R1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2172123	NM_024514.5(CYP2R1):c.582C>G (p.Ile194Met)	CYP2R1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2414155	NM_024514.5(CYP2R1):c.121C>A (p.Pro41Thr)	CYP2R1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CYP2R1	Strong	Autosomal recessive	vitamin D hydroxylation-deficient rickets, type 1B	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP2R1	Orphanet:289157	Hypocalcemic vitamin D-dependent rickets

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYP2R1	HGNC:20580	ENSG00000186104	Q6VVX0	Vitamin D 25-hydroxylase	gencc,clinvar
PDE3B	HGNC:8779	ENSG00000152270	Q13370	cGMP-inhibited 3’,5’-cyclic phosphodiesterase 3B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYP2R1	Vitamin D 25-hydroxylase	A cytochrome P450 monooxygenase involved in activation of vitamin D precursors.
PDE3B	cGMP-inhibited 3’,5’-cyclic phosphodiesterase 3B	Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological process.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYP2R1	Enzyme (other)	yes	1.14.14.24	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS
PDE3B	Transcription factor	no	3.1.4.17	PDEase_catalytic_dom, HD/PDEase_dom, PDEase_CS

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
male germ cell	1
sperm	1
adipose tissue	1
colonic epithelium	1
muscle layer of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYP2R1	252	ubiquitous	marker	sperm, male germ cell, left testis
PDE3B	216	ubiquitous	marker	colonic epithelium, muscle layer of sigmoid colon, adipose tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYP2R1	1,609
PDE3B	1,332

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PDE3B	Q13370	4
CYP2R1	Q6VVX0	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective CYP27B1 causes VDDR1B	1	5710.0×	9e-04	CYP2R1
PDE3B signalling	1	2855.0×	9e-04	PDE3B
Vitamins	1	951.7×	0.002	CYP2R1
Vitamin D (calciferol) metabolism	1	439.2×	0.003	CYP2R1
G alpha (s) signalling events	1	36.6×	0.027	PDE3B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to cesium ion	1	8426.0×	0.002	CYP2R1
calcitriol biosynthetic process from calciol	1	2808.7×	0.003	CYP2R1
vitamin metabolic process	1	1404.3×	0.004	CYP2R1
obsolete organic acid metabolic process	1	1203.7×	0.004	CYP2R1
negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	842.6×	0.004	PDE3B
vitamin D metabolic process	1	766.0×	0.004	CYP2R1
negative regulation of cell adhesion mediated by integrin	1	648.1×	0.004	PDE3B
negative regulation of lipid catabolic process	1	421.3×	0.005	PDE3B
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	351.1×	0.006	PDE3B
negative regulation of cAMP/PKA signal transduction	1	300.9×	0.006	PDE3B
regulation of angiogenesis	1	210.7×	0.007	PDE3B
response to ionizing radiation	1	205.5×	0.007	CYP2R1
negative regulation of cell adhesion	1	191.5×	0.007	PDE3B
insulin receptor signaling pathway	1	110.9×	0.012	PDE3B
negative regulation of angiogenesis	1	84.3×	0.014	PDE3B
xenobiotic metabolic process	1	74.6×	0.015	CYP2R1
angiogenesis	1	31.2×	0.034	PDE3B
G protein-coupled receptor signaling pathway	1	18.1×	0.054	PDE3B

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CYP2R1	PAZOPANIB
PDE3B	INAMRINONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDE3B	41	4
CYP2R1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PAZOPANIB	4	CYP2R1
INAMRINONE	4	PDE3B
VARDENAFIL	4	PDE3B
MILRINONE	4	PDE3B
LOSARTAN	4	PDE3B
SILDENAFIL	4	PDE3B
ENOXIMONE	4	PDE3B
CRISABOROLE	4	PDE3B
ANAGRELIDE	4	PDE3B
CILOSTAZOL	4	PDE3B
DIPYRIDAMOLE	4	PDE3B
LOSARTAN POTASSIUM	4	PDE3B
IBUDILAST	4	PDE3B
LEVOSIMENDAN	3	PDE3B
PAPAVERINE	3	PDE3B
IMAZODAN	2	PDE3B
MEDORINONE	2	PDE3B
OXAGRELATE	2	PDE3B
VESNARINONE	2	PDE3B
ISOMAZOLE	2	PDE3B
PIMOBENDAN	2	PDE3B
SULMAZOLE	2	PDE3B
BEMARINONE	2	PDE3B
SIMENDAN	2	PDE3B
ZARDAVERINE	2	PDE3B
QUAZINONE	2	PDE3B
CILOSTAMIDE	2	PDE3B
ETAZOLATE	2	PDE3B
CC-115	2	PDE3B
ORISMILAST	2	PDE3B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PDE3B	381	Binding:367, Functional:9, ADMET:5
CYP2R1	183	ADMET:181, Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP2R1	1.14.14.24	vitamin D 25-hydroxylase
PDE3B	3.1.4.17	3’,5’-cyclic-nucleotide phosphodiesterase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CYP2R1	183
PDE3B	381

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PAZOPANIB	4	CYP2R1
INAMRINONE	4	PDE3B
VARDENAFIL	4	PDE3B
MILRINONE	4	PDE3B
LOSARTAN	4	PDE3B
SILDENAFIL	4	PDE3B
ENOXIMONE	4	PDE3B
CRISABOROLE	4	PDE3B
ANAGRELIDE	4	PDE3B
CILOSTAZOL	4	PDE3B
DIPYRIDAMOLE	4	PDE3B
LOSARTAN POTASSIUM	4	PDE3B
IBUDILAST	4	PDE3B
LEVOSIMENDAN	3	PDE3B
PAPAVERINE	3	PDE3B
IMAZODAN	2	PDE3B
MEDORINONE	2	PDE3B
OXAGRELATE	2	PDE3B
VESNARINONE	2	PDE3B
ISOMAZOLE	2	PDE3B
PIMOBENDAN	2	PDE3B
SULMAZOLE	2	PDE3B
BEMARINONE	2	PDE3B
SIMENDAN	2	PDE3B
ZARDAVERINE	2	PDE3B
QUAZINONE	2	PDE3B
CILOSTAMIDE	2	PDE3B
ETAZOLATE	2	PDE3B
CC-115	2	PDE3B
ORISMILAST	2	PDE3B

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CYP2R1, PDE3B
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07366450	Not specified	NOT_YET_RECRUITING	High-Dose vs Standard Ergocalciferol for Vitamin D Normalization in Aggressive Non-Hodgkin Lymphoma
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

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CHOLECALCIFEROL	4	1