vitamin D-dependent rickets, type 2

Summary

vitamin D-dependent rickets, type 2 (MONDO:0019642) is a disease with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 2
• ClinVar variants: 1
• Phenotypes (HPO): 28

Clinical features

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0000843	Hyperparathyroidism	Very frequent (80-99%)
HP:0001373	Joint dislocation	Very frequent (80-99%)
HP:0002148	Hypophosphatemia	Very frequent (80-99%)
HP:0002653	Bone pain	Very frequent (80-99%)
HP:0002749	Osteomalacia	Very frequent (80-99%)
HP:0002757	Recurrent fractures	Very frequent (80-99%)
HP:0002797	Osteolysis	Very frequent (80-99%)
HP:0002901	Hypocalcemia	Very frequent (80-99%)
HP:0003330	Abnormal bone structure	Very frequent (80-99%)
HP:0012062	Bone cyst	Very frequent (80-99%)
HP:0100670	Rough bone trabeculation	Very frequent (80-99%)
HP:0000268	Dolichocephaly	Frequent (30-79%)
HP:0000765	Abnormal thorax morphology	Frequent (30-79%)
HP:0000787	Nephrolithiasis	Frequent (30-79%)
HP:0000944	Abnormal metaphysis morphology	Frequent (30-79%)
HP:0000951	Abnormality of the skin	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001596	Alopecia	Frequent (30-79%)
HP:0002970	Genu varum	Frequent (30-79%)
HP:0003272	Abnormality of the hip bone	Frequent (30-79%)
HP:0003312	Abnormal form of the vertebral bodies	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0006323	Premature loss of primary teeth	Frequent (30-79%)
HP:0009124	Abnormal adipose tissue morphology	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Occasional (5-29%)
HP:0002007	Frontal bossing	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002857	Genu valgum	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	vitamin D-dependent rickets, type 2
Mondo ID	MONDO:0019642
Orphanet	93160
ICD-11	2041886796
NCIT	C131077
SNOMED CT	72831007
UMLS	C3536983
MedGen	760752
GARD	0016805
Is cancer (heuristic)	no

Also known as: hereditary 1,25 dihydroxyvitamin D-resistant rickets with abnormal Vitamin D receptor · hereditary vitamin D-resistant rickets · HVDRR · hypocalcemic vitamin D-resistant rickets · VDDR II · VDDR2 · VDRR II · vitamin D dependent rickets 2 · vitamin D receptor deficiency · vitamin D-dependent rickets type II · vitamin D-dependent rickets, type 2 · vitamin D-resistant rickets type II

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

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 2

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

Subtypes (2): vitamin D-dependent rickets, type 2A, 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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
226119	NM_000444.6(PHEX):c.1735G>A (p.Gly579Arg)	PHEX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
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
PHEX	Orphanet:89936	X-linked hypophosphatemia

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
VDR	HGNC:12679	ENSG00000111424	P11473	Vitamin D3 receptor	gencc
PHEX	HGNC:8918	ENSG00000102174	P78562	Phosphate-regulating neutral endopeptidase PHEX	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.
PHEX	Phosphate-regulating neutral endopeptidase PHEX	Peptidase that cleaves SIBLING (small integrin-binding ligand, N-linked glycoprotein)-derived ASARM peptides, thus regulating their biological activity.

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
Nuclear receptor	1	192.9×	0.010
Protease	1	18.3×	0.054

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VDR	Nuclear receptor	yes		VitD_rcpt, Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt
PHEX	Protease	yes	3.4.24.B15	Peptidase_M13, Peptidase_M13_N, Peptidase_M13_C

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
tibia	2
hair follicle	1
jejunal mucosa	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VDR	224	ubiquitous	marker	tibia, hair follicle, jejunal mucosa
PHEX	139	tissue_specific	marker	secondary oocyte, tibia, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PHEX	856
VDR	354

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VDR	P11473	52

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PHEX	P78562	94.58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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
Vitamin D (calciferol) metabolism	1	878.5×	0.003	VDR
SUMOylation of intracellular receptors	1	335.9×	0.004	VDR
Nuclear Receptor transcription pathway	1	200.3×	0.005	VDR

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
organophosphate metabolic process	1	8426.0×	0.002	PHEX
nuclear receptor-mediated bile acid signaling pathway	1	4213.0×	0.002	VDR
response to bile acid	1	4213.0×	0.002	VDR
skeletal system development	2	125.8×	0.002	VDR, PHEX
apoptotic process involved in mammary gland involution	1	2808.7×	0.003	VDR
positive regulation of apoptotic process involved in mammary gland involution	1	2106.5×	0.003	VDR
mammary gland branching involved in pregnancy	1	2106.5×	0.003	VDR
vitamin D receptor signaling pathway	1	1404.3×	0.003	VDR
positive regulation of vitamin D receptor signaling pathway	1	1404.3×	0.003	VDR
response to insulin-like growth factor stimulus	1	1404.3×	0.003	PHEX
response to sodium phosphate	1	842.6×	0.004	PHEX
cellular response to vitamin D	1	766.0×	0.004	PHEX
cellular response to parathyroid hormone stimulus	1	702.2×	0.004	PHEX
phosphate ion transmembrane transport	1	601.9×	0.005	VDR
intestinal absorption	1	601.9×	0.005	VDR
response to growth hormone	1	561.7×	0.005	PHEX
intracellular receptor signaling pathway	1	495.6×	0.005	VDR
positive regulation of keratinocyte differentiation	1	401.2×	0.006	VDR
negative regulation of keratinocyte proliferation	1	351.1×	0.006	VDR
decidualization	1	337.0×	0.006	VDR
retinoic acid receptor signaling pathway	1	324.1×	0.006	VDR
odontogenesis	1	263.3×	0.007	PHEX
lactation	1	210.7×	0.008	VDR
positive regulation of bone mineralization	1	195.9×	0.009	VDR
mRNA transcription by RNA polymerase II	1	165.2×	0.010	VDR
bone development	1	138.1×	0.011	PHEX
bone mineralization	1	135.9×	0.011	PHEX
protein modification process	1	122.1×	0.012	PHEX
lung development	1	99.1×	0.014	PHEX
calcium ion transport	1	90.6×	0.015	VDR

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VDR	10	4
PHEX	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
CURCUMIN	3	VDR
SEOCALCITOL	3	VDR
MAXACALCITOL	3	VDR
TAUROLITHOCHOLIC ACID	3	VDR
TRICHOSTATIN	1	VDR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
VDR	561	Binding:459, Functional:99, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PHEX	3.4.24.B15

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
VDR	561

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

10 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
CURCUMIN	3	VDR
SEOCALCITOL	3	VDR
MAXACALCITOL	3	VDR
TAUROLITHOCHOLIC ACID	3	VDR
TRICHOSTATIN	1	VDR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	VDR
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PHEX
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)
PHEX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.