vitamin D-dependent rickets, type 1

Summary

vitamin D-dependent rickets, type 1 (MONDO:0009924) is a disease with 2 cohort genes.

At a glance

• Prevalence: 1-5 / 10 000 (Europe)
• Cohort genes: 2
• ClinVar variants: 45
• Phenotypes (HPO): 46

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

46 HPO clinical features (Orphanet curated; top 46 by frequency):

HPO ID	Term	Frequency
HP:0002748	Rickets	Obligate (100%)
HP:0002901	Hypocalcemia	Obligate (100%)
HP:0012052	Low serum calcitriol	Obligate (100%)
HP:0000867	Secondary hyperparathyroidism	Very frequent (80-99%)
HP:0000886	Deformed rib cage	Very frequent (80-99%)
HP:0000897	Rachitic rosary	Very frequent (80-99%)
HP:0000920	Enlargement of the costochondral junction	Very frequent (80-99%)
HP:0001270	Motor delay	Very frequent (80-99%)
HP:0001281	Tetany	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0002148	Hypophosphatemia	Very frequent (80-99%)
HP:0002653	Bone pain	Very frequent (80-99%)
HP:0002659	Increased susceptibility to fractures	Very frequent (80-99%)
HP:0002663	Delayed epiphyseal ossification	Very frequent (80-99%)
HP:0002749	Osteomalacia	Very frequent (80-99%)
HP:0002752	Sparse bone trabeculae	Very frequent (80-99%)
HP:0002753	Thin bony cortex	Very frequent (80-99%)
HP:0002909	Generalized aminoaciduria	Very frequent (80-99%)
HP:0002970	Genu varum	Very frequent (80-99%)
HP:0002980	Femoral bowing	Very frequent (80-99%)
HP:0002982	Tibial bowing	Very frequent (80-99%)
HP:0003020	Enlargement of the wrists	Very frequent (80-99%)
HP:0003029	Enlargement of the ankles	Very frequent (80-99%)
HP:0003106	Subperiosteal bone resorption	Very frequent (80-99%)
HP:0003165	Elevated circulating parathyroid hormone level	Very frequent (80-99%)
HP:0005042	Irregular, rachitic-like metaphyses	Very frequent (80-99%)
HP:0005469	Flat occiput	Very frequent (80-99%)
HP:0008897	Postnatal growth retardation	Very frequent (80-99%)
HP:0010537	Wide cranial sutures	Very frequent (80-99%)
HP:0010639	Elevated alkaline phosphatase of bone origin	Very frequent (80-99%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001638	Cardiomyopathy	Frequent (30-79%)
HP:0001931	Hypochromic anemia	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0003155	Elevated circulating alkaline phosphatase concentration	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0000684	Delayed eruption of teeth	Occasional (5-29%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0001538	Protuberant abdomen	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0001974	Leukocytosis	Occasional (5-29%)
HP:0002199	Hypocalcemic seizures	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0006297	Enamel hypoplasia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	vitamin D-dependent rickets, type 1
Mondo ID	MONDO:0009924
MeSH	C562688
Orphanet	289157
ICD-11	1270705227
NCIT	C131073
SNOMED CT	67049004
UMLS	C0268689
MedGen	124344
GARD	0017319
Is cancer (heuristic)	no

Also known as: 1 Alpha-hydroxylase deficiency · 1-alpha-hydroxylase deficiency · hypocalcemic vitamin D-dependent rickets · PDDRI · pseudo vitamin-D deficient rickets · pseudovitamin D-deficient rickets · selective 1-alpha, 25-hydroxyvitamin D3 deficiency · VDDI · VDDR-I · VDDR1 · vitamin D 1 Alpha-Hydroxylase deficiency · vitamin D dependent rickets type I · vitamin D-dependency type I · vitamin D-dependent rickets type 1

Data availability: 45 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone remodeling disease › rickets › hypocalcemic rickets › vitamin D-dependent rickets, type 1

Related subtypes (1): vitamin D-dependent rickets, type 2

Subtypes (2): vitamin D hydroxylation-deficient rickets, type 1B, vitamin D-dependent rickets, type 1A

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

45 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 10 conflicting classifications of pathogenicity, 4 likely pathogenic, 4 pathogenic/likely pathogenic, 3 pathogenic, 2 likely benign, 1 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
427832	NM_000785.3(CYP27B1):c.[1319_1325dupCCCACCC];[1358G>A]		Pathogenic	criteria provided, single submitter
1669	NM_000785.4(CYP27B1):c.1166G>A (p.Arg389His)	CYP27B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279798	NM_000785.4(CYP27B1):c.1319_1325dup (p.Phe443fs)	CYP27B1	Pathogenic	criteria provided, multiple submitters, no conflicts
380287	NM_000785.4(CYP27B1):c.305G>A (p.Gly102Glu)	CYP27B1	Pathogenic	criteria provided, single submitter
522958	NM_000785.4(CYP27B1):c.1375C>T (p.Arg459Cys)	CYP27B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802871	NM_000785.4(CYP27B1):c.1357C>T (p.Arg453Cys)	CYP27B1	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
1339453	NM_000785.4(CYP27B1):c.386C>T (p.Ala129Val)	CYP27B1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339454	NM_000785.4(CYP27B1):c.623G>T (p.Gly208Val)	CYP27B1	Likely pathogenic	criteria provided, single submitter
1339455	NM_000785.4(CYP27B1):c.1160A>C (p.Asn387Thr)	CYP27B1	Likely pathogenic	criteria provided, single submitter
1658	NM_000785.4(CYP27B1):c.320G>A (p.Arg107His)	CYP27B1	Likely pathogenic	criteria provided, single submitter
309995	NM_000785.4(CYP27B1):c.1505A>G (p.Asn502Ser)	CYP27B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309997	NM_000785.4(CYP27B1):c.1057C>G (p.Pro353Ala)	CYP27B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309998	NM_000785.4(CYP27B1):c.801C>T (p.His267=)	CYP27B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310001	NM_000785.4(CYP27B1):c.541G>T (p.Ala181Ser)	CYP27B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310003	NM_000785.4(CYP27B1):c.348C>T (p.His116=)	CYP27B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
749237	NM_000785.4(CYP27B1):c.386+10C>T	CYP27B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880897	NM_000785.4(CYP27B1):c.1286G>A (p.Arg429His)	CYP27B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880898	NM_000785.4(CYP27B1):c.1230G>C (p.Leu410=)	CYP27B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
882531	NM_000785.4(CYP27B1):c.318G>A (p.Glu106=)	CYP27B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
882532	NM_000785.4(CYP27B1):c.117C>T (p.Asp39=)	CYP27B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309987	NM_000785.4(CYP27B1):c.*722C>G	CYP27B1	Uncertain significance	criteria provided, single submitter
309988	NM_000785.4(CYP27B1):c.*635G>A	CYP27B1	Uncertain significance	criteria provided, single submitter
309989	NM_000785.4(CYP27B1):c.*472C>A	CYP27B1	Uncertain significance	criteria provided, single submitter
309990	NM_000785.4(CYP27B1):c.*446G>A	CYP27B1	Uncertain significance	criteria provided, single submitter
309992	NM_000785.4(CYP27B1):c.*301T>C	CYP27B1	Uncertain significance	criteria provided, single submitter
309993	NM_000785.4(CYP27B1):c.*295G>A	CYP27B1	Uncertain significance	criteria provided, single submitter
309994	NM_000785.4(CYP27B1):c.*76G>A	CYP27B1	Uncertain significance	criteria provided, single submitter
309996	NM_000785.4(CYP27B1):c.1385A>T (p.Glu462Val)	CYP27B1	Uncertain significance	criteria provided, single submitter
309999	NM_000785.4(CYP27B1):c.794A>T (p.Gln265Leu)	CYP27B1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
CYP27B1	Definitive	Autosomal recessive	vitamin D-dependent rickets, type 1A	3
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
CYP27B1	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
CYP27B1	HGNC:2606	ENSG00000111012	O15528	25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial	gencc,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.
CYP27B1	25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial	A cytochrome P450 monooxygenase involved in vitamin D metabolism and in calcium and phosphorus homeostasis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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)	2	12.0×	0.007

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
CYP27B1	Enzyme (other)	yes	1.14.15.18	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
kidney epithelium	1
metanephric glomerulus	1
nephron tubule	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
CYP27B1	175	broad	yes	nephron tubule, metanephric glomerulus, kidney epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYP27B1	2,173
CYP2R1	1,609

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CYP2R1	Q6VVX0	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CYP27B1	O15528	86.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Vitamins	2	1903.3×	9e-07	CYP2R1, CYP27B1
Vitamin D (calciferol) metabolism	2	878.5×	2e-06	CYP2R1, CYP27B1
Defective CYP27B1 causes VDDR1A	1	5710.0×	2e-04	CYP27B1
Defective CYP27B1 causes VDDR1B	1	5710.0×	2e-04	CYP2R1

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
calcitriol biosynthetic process from calciol	2	5617.3×	5e-07	CYP2R1, CYP27B1
vitamin metabolic process	2	2808.7×	1e-06	CYP2R1, CYP27B1
vitamin D metabolic process	2	1532.0×	3e-06	CYP2R1, CYP27B1
response to cesium ion	1	8426.0×	7e-04	CYP2R1
vitamin D catabolic process	1	2106.5×	0.002	CYP27B1
positive regulation of vitamin D receptor signaling pathway	1	1404.3×	0.003	CYP27B1
obsolete organic acid metabolic process	1	1203.7×	0.003	CYP2R1
cellular response to vitamin D	1	766.0×	0.004	CYP27B1
G1 to G0 transition	1	702.2×	0.004	CYP27B1
response to vitamin D	1	401.2×	0.005	CYP27B1
positive regulation of keratinocyte differentiation	1	401.2×	0.005	CYP27B1
regulation of bone mineralization	1	366.4×	0.005	CYP27B1
decidualization	1	337.0×	0.005	CYP27B1
response to type II interferon	1	263.3×	0.006	CYP27B1
calcium ion homeostasis	1	221.7×	0.007	CYP27B1
response to ionizing radiation	1	205.5×	0.007	CYP2R1
response to estrogen	1	172.0×	0.008	CYP27B1
bone mineralization	1	135.9×	0.009	CYP27B1
calcium ion transport	1	90.6×	0.013	CYP27B1
xenobiotic metabolic process	1	74.6×	0.015	CYP2R1
negative regulation of cell growth	1	72.0×	0.015	CYP27B1
response to lipopolysaccharide	1	62.4×	0.017	CYP27B1
negative regulation of cell population proliferation	1	21.1×	0.047	CYP27B1

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
CYP27B1	KETOCONAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP2R1	1	4
CYP27B1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PAZOPANIB	4	CYP2R1
KETOCONAZOLE	4	CYP27B1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CYP2R1	183	ADMET:181, Binding:2
CYP27B1	7	Binding:6, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP2R1	1.14.14.24	vitamin D 25-hydroxylase
CYP27B1	1.14.15.18	calcidiol 1-monooxygenase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CYP2R1	183

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

2 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
KETOCONAZOLE	4	CYP27B1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CYP2R1, CYP27B1
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: 0.