vitamin D-dependent rickets, type 2A

Summary

vitamin D-dependent rickets, type 2A (MONDO:0010186) is a disease caused by VDR (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: VDR (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 235

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	vitamin D-dependent rickets, type 2A
Mondo ID	MONDO:0010186
MeSH	C562794
OMIM	277440
DOID	DOID:0080884
NCIT	C131075
SNOMED CT	237894002
UMLS	C0342646
MedGen	90989
GARD	0018169
Is cancer (heuristic)	no

Also known as: generalised resistance to 1,25-dihydroxyvitamin D · hereditary 1,25 dihydroxyvitamin D-resistant rickets with abnormal vitamin D receptor with alopecia · rickets, vitamin D-resistant, type IIA · VDDR2A · VDR vitamin D-dependent rickets, type 2 · vitamin D dependent rickets 2a · vitamin D receptor deficiency rickets · vitamin d-dependent rickets type II with alopecia · vitamin D-dependent rickets, type 2 caused by mutation in VDR · vitamin D-dependent rickets, type 2A

Data availability: 235 ClinVar variants · 3 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 2 › vitamin D-dependent rickets, type 2A

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

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

235 retrieved; paginated sample, class counts are floors:

147 uncertain significance, 32 conflicting classifications of pathogenicity, 17 pathogenic, 14 benign, 12 likely benign, 9 likely pathogenic, 2 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1343092	NM_000376.3(VDR):c.148C>T (p.Arg50Ter)	VDR	Pathogenic	criteria provided, multiple submitters, no conflicts
1686293	NM_000376.3(VDR):c.217C>T (p.Arg73Ter)	VDR	Pathogenic	criteria provided, multiple submitters, no conflicts
2137319	NM_000376.3(VDR):c.1172G>A (p.Arg391His)	VDR	Pathogenic	criteria provided, multiple submitters, no conflicts
2506489	NM_000376.3(VDR):c.856T>C (p.Trp286Arg)	VDR	Pathogenic	criteria provided, single submitter
264696	NM_000376.3(VDR):c.1171C>A (p.Arg391Ser)	VDR	Pathogenic	no assertion criteria provided
264697	NM_000376.3(VDR):c.1190A>C (p.His397Pro)	VDR	Pathogenic	no assertion criteria provided
7745	NM_000376.3(VDR):c.98G>A (p.Gly33Asp)	VDR	Pathogenic	no assertion criteria provided
7746	NM_000376.3(VDR):c.218G>A (p.Arg73Gln)	VDR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7747	NM_000376.3(VDR):c.885C>A (p.Tyr295Ter)	VDR	Pathogenic	criteria provided, multiple submitters, no conflicts
7748	NM_000376.3(VDR):c.985G>A (p.Glu329Lys)	VDR	Pathogenic	no assertion criteria provided
7750	NM_000376.3(VDR):c.149G>A (p.Arg50Gln)	VDR	Pathogenic	no assertion criteria provided
7751	NM_000376.3(VDR):c.454C>T (p.Gln152Ter)	VDR	Pathogenic	no assertion criteria provided
7752	NM_000376.3(VDR):c.821G>T (p.Arg274Leu)	VDR	Pathogenic	no assertion criteria provided
7753	NM_000376.3(VDR):c.137G>A (p.Gly46Asp)	VDR	Pathogenic	no assertion criteria provided
7754	NM_000376.3(VDR):c.915C>G (p.His305Gln)	VDR	Pathogenic	no assertion criteria provided
7756	NM_000376.3(VDR):c.1171C>T (p.Arg391Cys)	VDR	Pathogenic	criteria provided, single submitter
7757	NM_000376.3(VDR):c.88C>T (p.Arg30Ter)	VDR	Pathogenic	criteria provided, multiple submitters, no conflicts
7758	NM_000376.3(VDR):c.366del (p.Lys123fs)	VDR	Pathogenic	no assertion criteria provided
915348	NM_000376.3(VDR):c.821G>A (p.Arg274His)	VDR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343093	NM_000376.3(VDR):c.-45A>G	VDR	Likely pathogenic	criteria provided, single submitter
2434513	NM_000376.3(VDR):c.146+1G>T	VDR	Likely pathogenic	criteria provided, single submitter
2691486	NM_000376.3(VDR):c.-2-1G>A	VDR	Likely pathogenic	criteria provided, single submitter
3574597	NM_000376.3(VDR):c.1024+1G>A	VDR	Likely pathogenic	criteria provided, single submitter
3574599	NM_000376.3(VDR):c.937del (p.Leu313fs)	VDR	Likely pathogenic	criteria provided, single submitter
3775554	NM_000376.3(VDR):c.1153C>T (p.Gln385Ter)	VDR	Likely pathogenic	criteria provided, single submitter
381603	NM_000376.3(VDR):c.1027C>T (p.Arg343Cys)	VDR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4072360	NM_000376.3(VDR):c.379G>T (p.Glu127Ter)	VDR	Likely pathogenic	criteria provided, single submitter
7759	NM_000376.3(VDR):c.1036G>A (p.Val346Met)	VDR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
198539	NM_006214.4(PHYH):c.734G>A (p.Arg245Gln)	PHYH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
11877	NM_002769.5(PRSS1):c.86A>T (p.Asn29Ile)	PRSS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · 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
VDR	Definitive	Autosomal recessive	vitamin D-dependent rickets, type 2A	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VDR	Orphanet:93160	Hypocalcemic vitamin D-resistant rickets
PHYH	Orphanet:773	Adult Refsum disease
PRSS1	Orphanet:676	Autosomal dominant hereditary chronic pancreatitis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VDR	HGNC:12679	ENSG00000111424	P11473	Vitamin D3 receptor	gencc,clinvar
PHYH	HGNC:8940	ENSG00000107537	O14832	Phytanoyl-CoA dioxygenase, peroxisomal	clinvar
PRSS1	HGNC:9475	ENSG00000204983	P07477	Serine protease 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VDR	Vitamin D3 receptor	Nuclear receptor for calcitriol, the active form of vitamin D3 which mediates the action of this vitamin on cells.
PHYH	Phytanoyl-CoA dioxygenase, peroxisomal	Catalyzes the 2-hydroxylation of not only racemic phytanoyl-CoA and the isomers of 3-methylhexadecanoyl-CoA, but also a variety of other mono-branched 3-methylacyl-CoA esters (with a chain length of at least seven carbon atoms) and straigh…
PRSS1	Serine protease 1	Has activity against the synthetic substrates Boc-Phe-Ser-Arg-Mec, Boc-Leu-Thr-Arg-Mec, Boc-Gln-Ala-Arg-Mec and Boc-Val-Pro-Arg-Mec.

Protein-family classification

Druggable: 3 · 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
Nuclear receptor	1	128.6×	0.023
Protease	1	12.2×	0.120
Enzyme (other)	1	4.0×	0.230

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VDR	Nuclear receptor	yes		VitD_rcpt, Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt
PHYH	Enzyme (other)	yes	1.14.11.18	Phytyl_CoA_dOase-like, PhyH
PRSS1	Protease	yes		Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hair follicle	1
jejunal mucosa	1
tibia	1
biceps brachii	1
quadriceps femoris	1
vastus lateralis	1
body of pancreas	1
islet of Langerhans	1
pancreas	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VDR	224	ubiquitous	marker	tibia, hair follicle, jejunal mucosa
PHYH	296	ubiquitous	marker	vastus lateralis, biceps brachii, quadriceps femoris
PRSS1	127	tissue_specific	marker	body of pancreas, pancreas, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PHYH	1,777
PRSS1	1,363
VDR	354

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VDR	P11473	52
PRSS1	P07477	12
PHYH	O14832	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Alpha-oxidation of phytanate	1	634.4×	0.008	PHYH
TYSND1 cleaves peroxisomal proteins	1	475.8×	0.008	PHYH
Uptake of dietary cobalamins into enterocytes	1	380.7×	0.008	PRSS1
Vitamin D (calciferol) metabolism	1	292.8×	0.008	VDR
SUMOylation of intracellular receptors	1	112.0×	0.013	VDR
Activation of Matrix Metalloproteinases	1	102.9×	0.013	PRSS1
Developmental Lineage of Pancreatic Acinar Cells	1	100.2×	0.013	PRSS1
Nuclear Receptor transcription pathway	1	66.8×	0.017	VDR
Peroxisomal protein import	1	57.7×	0.017	PHYH

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
2-oxobutyrate catabolic process	1	5617.3×	0.004	PHYH
nuclear receptor-mediated bile acid signaling pathway	1	2808.7×	0.004	VDR
response to bile acid	1	2808.7×	0.004	VDR
apoptotic process involved in mammary gland involution	1	1872.4×	0.004	VDR
methyl-branched fatty acid metabolic process	1	1872.4×	0.004	PHYH
positive regulation of apoptotic process involved in mammary gland involution	1	1404.3×	0.004	VDR
mammary gland branching involved in pregnancy	1	1404.3×	0.004	VDR
isoprenoid metabolic process	1	1123.5×	0.004	PHYH
vitamin D receptor signaling pathway	1	936.2×	0.004	VDR
positive regulation of vitamin D receptor signaling pathway	1	936.2×	0.004	VDR
fatty acid alpha-oxidation	1	802.5×	0.004	PHYH
phosphate ion transmembrane transport	1	401.2×	0.007	VDR
intestinal absorption	1	401.2×	0.007	VDR
intracellular receptor signaling pathway	1	330.4×	0.007	VDR
2-oxoglutarate metabolic process	1	312.1×	0.007	PHYH
positive regulation of keratinocyte differentiation	1	267.5×	0.008	VDR
negative regulation of keratinocyte proliferation	1	234.1×	0.008	VDR
decidualization	1	224.7×	0.008	VDR
retinoic acid receptor signaling pathway	1	216.1×	0.008	VDR
digestion	1	208.1×	0.008	PRSS1
lactation	1	140.4×	0.012	VDR
positive regulation of bone mineralization	1	130.6×	0.012	VDR
extracellular matrix disassembly	1	122.1×	0.012	PRSS1
mRNA transcription by RNA polymerase II	1	110.1×	0.013	VDR
calcium ion transport	1	60.4×	0.023	VDR
cell morphogenesis	1	52.5×	0.025	VDR
intracellular calcium ion homeostasis	1	48.4×	0.027	VDR
skeletal system development	1	41.9×	0.030	VDR
negative regulation of cell population proliferation	1	14.0×	0.084	VDR
positive regulation of gene expression	1	12.9×	0.088	VDR

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
VDR	CHOLECALCIFEROL
PRSS1	ARGATROBAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRSS1	17	4
VDR	10	4
PHYH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CHOLECALCIFEROL	4	VDR
CALCIPOTRIENE	4	VDR
DOXERCALCIFEROL	4	VDR
TACALCITOL	4	VDR
CALCITRIOL	4	VDR
ARGATROBAN	4	PRSS1
MELAGATRAN	4	PRSS1
SULFAGUANIDINE	4	PRSS1
BEROTRALSTAT	4	PRSS1
CURCUMIN	3	VDR
SEOCALCITOL	3	VDR
MAXACALCITOL	3	VDR
TAUROLITHOCHOLIC ACID	3	VDR
NAFAMOSTAT	3	PRSS1
OTAMIXABAN	3	PRSS1
CAMOSTAT	3	PRSS1
CAMOSTAT MESILATE	3	PRSS1
RUTIN	3	PRSS1
MILVEXIAN	3	PRSS1
DABIGATRAN	3	PRSS1
QUERCETIN	3	PRSS1
SILIBININ	3	PRSS1
EFEGATRAN	2	PRSS1
SEPIMOSTAT	2	PRSS1
BAICALEIN	2	PRSS1
TRICHOSTATIN	1	VDR
AZD-8165	1	PRSS1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PRSS1	674	Binding:616, ADMET:51, Functional:7
VDR	561	Binding:459, Functional:99, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PHYH	1.14.11.18	phytanoyl-CoA dioxygenase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
VDR	561
PRSS1	674

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

27 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)
CHOLECALCIFEROL	4	VDR
CALCIPOTRIENE	4	VDR
DOXERCALCIFEROL	4	VDR
TACALCITOL	4	VDR
CALCITRIOL	4	VDR
ARGATROBAN	4	PRSS1
MELAGATRAN	4	PRSS1
SULFAGUANIDINE	4	PRSS1
BEROTRALSTAT	4	PRSS1
CURCUMIN	3	VDR
SEOCALCITOL	3	VDR
MAXACALCITOL	3	VDR
TAUROLITHOCHOLIC ACID	3	VDR
NAFAMOSTAT	3	PRSS1
OTAMIXABAN	3	PRSS1
CAMOSTAT	3	PRSS1
CAMOSTAT MESILATE	3	PRSS1
RUTIN	3	PRSS1
MILVEXIAN	3	PRSS1
DABIGATRAN	3	PRSS1
QUERCETIN	3	PRSS1
SILIBININ	3	PRSS1
EFEGATRAN	2	PRSS1
SEPIMOSTAT	2	PRSS1
BAICALEIN	2	PRSS1
TRICHOSTATIN	1	VDR
AZD-8165	1	PRSS1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	VDR, PRSS1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PHYH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PHYH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.