vitamin D-dependent rickets, type 1A

Summary

vitamin D-dependent rickets, type 1A (MONDO:0020723) is a disease caused by CYP27B1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: CYP27B1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 140

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	vitamin D-dependent rickets, type 1A
Mondo ID	MONDO:0020723
OMIM	264700
DOID	DOID:0080886
GARD	0018636
Is cancer (heuristic)	no

Also known as: VDDR1A · vitamin D hydroxylation-deficient rickets, type 1A · vitamin D-dependent rickets, type 1A · vitamin D-dependent rickets, type I

Data availability: 140 ClinVar variants · 2 GenCC gene-disease records.

Disease family

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 › vitamin D-dependent rickets, type 1A

Related subtypes (1): vitamin D hydroxylation-deficient rickets, type 1B

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

140 retrieved; paginated sample, class counts are floors:

60 uncertain significance, 30 likely pathogenic, 21 pathogenic, 11 pathogenic/likely pathogenic, 8 conflicting classifications of pathogenicity, 5 likely benign, 2 benign/likely benign, 2 benign, 1 likely risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
1007304	NM_000785.4(CYP27B1):c.1376G>A (p.Arg459His)	CYP27B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069143	NM_000785.4(CYP27B1):c.160_161dup (p.Lys55fs)	CYP27B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1228385	NM_000785.4(CYP27B1):c.497_500del (p.Val166fs)	CYP27B1	Pathogenic	criteria provided, single submitter
1322185	NM_000785.4(CYP27B1):c.403C>T (p.Gln135Ter)	CYP27B1	Pathogenic	criteria provided, single submitter
1324206	NM_000785.4(CYP27B1):c.1165C>T (p.Arg389Cys)	CYP27B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1457495	NM_000785.4(CYP27B1):c.170G>T (p.Gly57Val)	CYP27B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1660	NM_000785.4(CYP27B1):c.1004G>C (p.Arg335Pro)	CYP27B1	Pathogenic	no assertion criteria provided
1662	NM_000785.4(CYP27B1):c.631del (p.Glu211fs)	CYP27B1	Pathogenic	criteria provided, single submitter
1663	NM_000785.4(CYP27B1):c.693del (p.Thr232fs)	CYP27B1	Pathogenic	no assertion criteria provided
1664	NM_000785.4(CYP27B1):c.262del (p.Val88fs)	CYP27B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1666	NM_000785.4(CYP27B1):c.962C>G (p.Thr321Arg)	CYP27B1	Pathogenic	no assertion criteria provided
1667	NM_000785.4(CYP27B1):c.589+1G>A	CYP27B1	Pathogenic	criteria provided, single submitter
1668	NM_000785.4(CYP27B1):c.1226C>T (p.Thr409Ile)	CYP27B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1669	NM_000785.4(CYP27B1):c.1166G>A (p.Arg389His)	CYP27B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1670	NM_000785.4(CYP27B1):c.201_204delinsCTTCG (p.Gln67fs)	CYP27B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1672	NM_000785.4(CYP27B1):c.1165C>G (p.Arg389Gly)	CYP27B1	Pathogenic	no assertion criteria provided
1673	NM_000785.4(CYP27B1):c.1027C>T (p.Leu343Phe)	CYP27B1	Pathogenic	no assertion criteria provided
1685687	NM_000785.4(CYP27B1):c.252_262del (p.Thr85fs)	CYP27B1	Pathogenic	criteria provided, single submitter
1705730	NM_000785.4(CYP27B1):c.335C>T (p.Pro112Leu)	CYP27B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1931662	NM_000785.4(CYP27B1):c.171del (p.Leu58fs)	CYP27B1	Pathogenic	criteria provided, multiple submitters, no conflicts
265095	NM_000785.4(CYP27B1):c.1286G>C (p.Arg429Pro)	CYP27B1	Pathogenic	criteria provided, multiple submitters, no conflicts
267276	NM_000785.4(CYP27B1):c.1358G>A (p.Arg453His)	CYP27B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2735903	NM_000785.4(CYP27B1):c.1294C>T (p.Arg432Cys)	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
2888336	NM_000785.4(CYP27B1):c.57_69del (p.Glu20fs)	CYP27B1	Pathogenic	criteria provided, multiple submitters, no conflicts
3251601	NM_000785.4(CYP27B1):c.1376G>T (p.Arg459Leu)	CYP27B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3367183	NM_000785.4(CYP27B1):c.48_60del (p.Glu20fs)	CYP27B1	Pathogenic	criteria provided, single submitter
3385177	NC_000012.11:g.(?58156116)(58160862_?)del	CYP27B1	Pathogenic	criteria provided, single submitter
595816	NM_000785.4(CYP27B1):c.171dup (p.Leu58fs)	CYP27B1	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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
CYP27B1	Definitive	Autosomal recessive	vitamin D-dependent rickets, type 1A	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP27B1	Orphanet:289157	Hypocalcemic vitamin D-dependent rickets

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
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)
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: 1 · 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)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
kidney epithelium	1
metanephric glomerulus	1
nephron tubule	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CYP27B1	O15528	86.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 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 1 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 VDDR1A	1	11420.0×	3e-04	CYP27B1
Vitamins	1	1903.3×	8e-04	CYP27B1
Vitamin D (calciferol) metabolism	1	878.5×	0.001	CYP27B1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 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	1	5617.3×	0.002	CYP27B1
vitamin D catabolic process	1	4213.0×	0.002	CYP27B1
vitamin metabolic process	1	2808.7×	0.002	CYP27B1
positive regulation of vitamin D receptor signaling pathway	1	2808.7×	0.002	CYP27B1
vitamin D metabolic process	1	1532.0×	0.002	CYP27B1
cellular response to vitamin D	1	1532.0×	0.002	CYP27B1
G1 to G0 transition	1	1404.3×	0.002	CYP27B1
response to vitamin D	1	802.5×	0.003	CYP27B1
positive regulation of keratinocyte differentiation	1	802.5×	0.003	CYP27B1
regulation of bone mineralization	1	732.7×	0.003	CYP27B1
decidualization	1	674.1×	0.003	CYP27B1
response to type II interferon	1	526.6×	0.003	CYP27B1
calcium ion homeostasis	1	443.5×	0.003	CYP27B1
response to estrogen	1	343.9×	0.004	CYP27B1
bone mineralization	1	271.8×	0.005	CYP27B1
calcium ion transport	1	181.2×	0.007	CYP27B1
negative regulation of cell growth	1	144.0×	0.008	CYP27B1
response to lipopolysaccharide	1	124.8×	0.008	CYP27B1
negative regulation of cell population proliferation	1	42.1×	0.024	CYP27B1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
CYP27B1	KETOCONAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP27B1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KETOCONAZOLE	4	CYP27B1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CYP27B1	7	Binding:6, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP27B1	1.14.15.18	calcidiol 1-monooxygenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
KETOCONAZOLE	4	CYP27B1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	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.