Hypercalcemia disease

Summary

Hypercalcemia disease (MONDO:0001566) is a disease with 1 cohort gene and 30 clinical trials. Top therapeutic interventions include cinacalcet, cholecalciferol, and paricalcitol.

At a glance

• Cohort genes: 1
• ClinVar variants: 6
• Clinical trials: 30

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypercalcemia disease
Mondo ID	MONDO:0001566
MeSH	D006934
DOID	DOID:12678
ICD-10-CM	E83.52
NCIT	C3112
SNOMED CT	66931009
UMLS	C0020437
MedGen	5686
Is cancer (heuristic)	no

Also known as: hypercalcemia

Data availability: 6 ClinVar variants · 1 HPO phenotype.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › mineral metabolism disease › calcium metabolic disease › hypercalcemia disease

Related subtypes (3): calcinosis, autosomal dominant hypocalcemia, calcium-alkali syndrome

Subtypes (3): hypercalcemia, infantile, familial hypocalciuric hypercalcemia, humoral hypercalcemia of malignancy

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

6 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 1 likely benign, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
374153	NM_000388.4(CASR):c.2449G>A (p.Val817Ile)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
35803	NM_000388.4(CASR):c.974G>A (p.Gly325Glu)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1497032	NM_000388.4(CASR):c.1377G>A (p.Gln459=)	CASR	Uncertain significance	criteria provided, multiple submitters, no conflicts
419926	NM_000388.4(CASR):c.566A>G (p.Asn189Ser)	CASR	Uncertain significance	criteria provided, multiple submitters, no conflicts
420662	NM_000388.4(CASR):c.2540G>A (p.Gly847Asp)	CASR	Uncertain significance	criteria provided, multiple submitters, no conflicts
1129430	NM_000388.4(CASR):c.1212C>T (p.Val404=)	CASR	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CASR	Orphanet:417	Neonatal severe primary hyperparathyroidism
CASR	Orphanet:428	Autosomal dominant hypocalcemia
CASR	Orphanet:676	Autosomal dominant hereditary chronic pancreatitis
CASR	Orphanet:93372	Familial hypocalciuric hypercalcemia type 1

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
CASR	HGNC:1514	ENSG00000036828	P41180	Extracellular calcium-sensing receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CASR	Extracellular calcium-sensing receptor	G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium 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
GPCR	1	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CASR	GPCR	yes		GPCR_3_Ca_sens_rcpt-rel, GPCR_3, ANF_lig-bd_rcpt

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
diaphragm	1
hair follicle	1
islet of Langerhans	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CASR	63	tissue_specific	marker	islet of Langerhans, diaphragm, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CASR	2,692

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CASR	P41180	31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Class C/3 (Metabotropic glutamate/pheromone receptors)	1	292.8×	0.024	CASR
GPCR ligand binding	1	64.2×	0.030	CASR
G alpha (q) signalling events	1	57.4×	0.030	CASR
GPCR downstream signalling	1	43.4×	0.030	CASR
Signaling by GPCR	1	40.1×	0.030	CASR
G alpha (i) signalling events	1	39.0×	0.030	CASR
Signal Transduction	1	10.2×	0.098	CASR

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
regulation of presynaptic membrane potential	1	8426.0×	0.003	CASR
chemosensory behavior	1	3370.4×	0.003	CASR
bile acid secretion	1	3370.4×	0.003	CASR
response to fibroblast growth factor	1	2106.5×	0.003	CASR
fat pad development	1	1685.2×	0.003	CASR
cellular response to peptide	1	1685.2×	0.003	CASR
cellular response to vitamin D	1	1532.0×	0.003	CASR
positive regulation of positive chemotaxis	1	1404.3×	0.003	CASR
detection of calcium ion	1	1123.5×	0.003	CASR
cellular response to hepatocyte growth factor stimulus	1	1123.5×	0.003	CASR
positive regulation of calcium ion import	1	936.2×	0.003	CASR
cellular response to low-density lipoprotein particle stimulus	1	887.0×	0.003	CASR
regulation of calcium ion transport	1	802.5×	0.003	CASR
branching morphogenesis of an epithelial tube	1	732.7×	0.003	CASR
positive regulation of vasoconstriction	1	601.9×	0.003	CASR
positive regulation of NLRP3 inflammasome complex assembly	1	581.1×	0.003	CASR
vasodilation	1	366.4×	0.005	CASR
JNK cascade	1	271.8×	0.006	CASR
cellular response to glucose stimulus	1	267.5×	0.006	CASR
positive regulation of insulin secretion	1	255.3×	0.006	CASR
response to ischemia	1	251.5×	0.006	CASR
chloride transmembrane transport	1	237.3×	0.006	CASR
ossification	1	227.7×	0.006	CASR
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	218.9×	0.006	CASR
intracellular calcium ion homeostasis	1	145.3×	0.009	CASR
anatomical structure morphogenesis	1	139.3×	0.009	CASR
phospholipase C-activating G protein-coupled receptor signaling pathway	1	131.7×	0.009	CASR
cellular response to hypoxia	1	121.2×	0.009	CASR
positive regulation of ERK1 and ERK2 cascade	1	85.1×	0.013	CASR
positive regulation of gene expression	1	38.7×	0.028	CASR

Therapeutics

Drugs indicated or in trials for this disease

6 approved drugs — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Calcitonin Salmon	Approved (phase 4)
Cortisone Acetate	Approved (phase 4)
Denosumab	Approved (phase 4)
Dexamethasone	Approved (phase 4)
Prednisolone	Approved (phase 4)
Prednisone	Approved (phase 4)

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
CASR	CINACALCET HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CASR	10	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CINACALCET HYDROCHLORIDE	4	CASR
CINACALCET	4	CASR
ENCALERET	3	CASR
EVOCALCET	3	CASR
SB-423562	2	CASR
RONACALERET	2	CASR
TECALCET HYDROCHLORIDE	2	CASR
FENDILINE	2	CASR
TECALCET	2	CASR
ATF-936	1	CASR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CASR	45	Functional:32, Binding:13

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

9 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)
CINACALCET HYDROCHLORIDE	4	CASR
ENCALERET	3	CASR
EVOCALCET	3	CASR
SB-423562	2	CASR
RONACALERET	2	CASR
TECALCET HYDROCHLORIDE	2	CASR
FENDILINE	2	CASR
TECALCET	2	CASR
ATF-936	1	CASR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CASR
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: 30.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	18
PHASE4	4
PHASE3	3
PHASE2/PHASE3	2
PHASE2	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03935984	PHASE4	RECRUITING	Calcitonin Pre-treatment to Improve SPECT-CT Sensitivity
NCT00581828	PHASE4	COMPLETED	Does Treatment of Hypovitaminosis D Increase Calcium Absorption?
NCT00891813	PHASE4	COMPLETED	Effectiveness and Safety of IV Zemplar in Patients on Hemodialysis and With Secondary Hyperparathyroidism Using iPTH/100 as Initial Dose
NCT01725113	PHASE4	TERMINATED	Management of Mineral and Bone Disease in Hemodialysis-Calcitriol vs. Paricalcitol
NCT00325104	PHASE3	COMPLETED	Cinacalcet to Treat Familial Primary Hyperparathyroidism
NCT00674154	PHASE2/PHASE3	COMPLETED	Effect of Vitamin D Treatment in Primary Hyperparathyroidism
NCT00975221	PHASE3	COMPLETED	Efficacy and Safety Study of Cinacalcet for the Treatment of Hypercalcemia in Patients With Primary Hyperparathyroidism Unable to Undergo Parathyroidectomy
NCT01329666	PHASE2/PHASE3	WITHDRAWN	Primary Hyperparathyroidism (PHPT): Early Effect of Vitamin D
NCT01460030	PHASE3	COMPLETED	An Intra-individual Titration Study of KRN1493 for the Treatment of Hypercalcemia in Patients With Parathyroid Carcinoma or Intractable Primary Hyperparathyroidism
NCT00001277	PHASE2	COMPLETED	Studies of Elevated Parathyroid Activity
NCT00415584	PHASE1/PHASE2	TERMINATED	Cinacalcet to Treat Hypercalcemia in Renal Transplant Recipients
NCT00744302	PHASE2	COMPLETED	Study of 1.25 mmol/L Calcium Dialysate on Mineral Metabolism in Haemodialysis Patients.
NCT04265599	Not specified	RECRUITING	Exploring Pathogenesis and Treatment of Hypercalcemia Caused by Intramuscular Injection of Paraffinoil
NCT04292288	Not specified	RECRUITING	Hypercalcemia After Paraffin Oil Injection
NCT05585593	Not specified	RECRUITING	Registry for Hypoparathyroidism Wuerzburg
NCT06467877	Not specified	ACTIVE_NOT_RECRUITING	Causes, Characteristics and Treatment of Hypercalcemia in the Emergency Room of a German Hospital
NCT06763549	Not specified	ENROLLING_BY_INVITATION	COR-INSIGHT: Optimizing Cardiovascular and Cardiopulmonary Outcomes with AI-Driven Multiplexed Indications Using COR ECG Wearable
NCT00126386	Not specified	COMPLETED	Zometa for the Management of Tumor-induced Hypercalcemia and Malignant Bone Pain in the Community
NCT00485706	Not specified	COMPLETED	Arterial Stiffness and Decreased Bone Buffering Capacity in Hemodialysis Patients
NCT01021280	Not specified	UNKNOWN	Parathyroid Hormone (PTH) Homeostasis in Bartter Syndrome
NCT01042626	Not specified	COMPLETED	Oral Peptones Load in Normocalcemic and Hypercalcemic Primary Hyperparathyroidism and Healthy Subjects
NCT01226810	Not specified	UNKNOWN	The Novel Approach of Minimally Invasive Parathyroid Surgery Requires Precise Identification and Localization of the Lesion Prior to Exploration
NCT01647503	Not specified	UNKNOWN	Differentially Expressed Proteins in Sporadic Parathyroid Tumors
NCT02711059	Not specified	WITHDRAWN	Insulin Resistance in Primary Hyperparathyroidism
NCT02908542	Not specified	COMPLETED	Search for New Genetic Causes of Hypercalcemia by Massively Parallel Sequencing of a Genes Panel
NCT03516747	Not specified	WITHDRAWN	Preoperational Fine Needle Aspiration of Pathological Parathyroid Gland
NCT04256369	Not specified	COMPLETED	Rate of Termination of Premixed Parenteral Nutrition (PN) in Surgical Patients Secondary to High Serum Electrolytes
NCT04299425	Not specified	COMPLETED	Evaluating Impact of NIRAF Detection for Identifying Parathyroid Glands During Parathyroidectomy
NCT05022641	Not specified	COMPLETED	Evaluating Impact of Near Infrared Autofluorescence (NIRAF) Detection for Identifying Parathyroid Glands During Parathyroidectomy
NCT05152927	Not specified	COMPLETED	Near Infrared Autofluorescence (NIRAF) Detection for Identifying Parathyroid Glands During Parathyroidectomy

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CINACALCET	4	5
CHOLECALCIFEROL	4	3
PARICALCITOL	4	2
CALCITONIN	4	1
CALCITRIOL	4	1
EDOTREOTIDE GALLIUM GA-68	4	1
ERGOCALCIFEROL	4	1
FLUORODOPA F 18	4	1
PARATHYROID HORMONE	4	1