CASR

Summary

CASR (calcium sensing receptor, HGNC:1514) is a protein-coding gene on chromosome 3q13.33-q21.1, encoding Extracellular calcium-sensing receptor (P41180). G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis.

The protein encoded by this gene is a plasma membrane G protein-coupled receptor that senses small changes in circulating calcium concentration. The encoded protein couples this information to intracellular signaling pathways that modify parathyroid hormone secretion or renal cation handling, and thus this protein plays an essential role in maintaining mineral ion homeostasis. Mutations in this gene are a cause of familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia.

Source: NCBI Gene 846 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neonatal severe primary hyperparathyroidism (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 19
• Clinical variants (ClinVar): 3,104 total — 186 pathogenic, 97 likely-pathogenic
• Phenotypes (HPO): 89
• Druggable target: yes — 10 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000388

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1514
Approved symbol	CASR
Name	calcium sensing receptor
Location	3q13.33-q21.1
Locus type	gene with protein product
Status	Approved
Aliases	FHH, NSHPT, GPRC2A
Ensembl gene	ENSG00000036828
Ensembl biotype	protein_coding
OMIM	601199
Entrez	846

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000490131, ENST00000498619, ENST00000638296, ENST00000638421, ENST00000639785, ENST00000643573, ENST00000851099, ENST00000851100

RefSeq mRNA: 2 — MANE Select: NM_000388 NM_000388, NM_001178065

CCDS: CCDS3010, CCDS54632

Canonical transcript exons

ENST00000639785 — 7 exons

Exon	Start	End
ENSE00000776614	122282113	122282236
ENSE00001252008	122253948	122254374
ENSE00001325686	122257081	122257387
ENSE00003797931	122275812	122276042
ENSE00003804122	122261528	122262412
ENSE00003807638	122283687	122291629
ENSE00003808587	122183668	122183812

Expression profiles

Bgee: expression breadth broad, 63 present calls, max score 93.53.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0711 / max 16.1760, expressed in 18 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38223	0.0460	14
38224	0.0119	8
38226	0.0076	3
38225	0.0057	2

Top tissues by expression

241 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	93.53	gold quality
diaphragm	UBERON:0001103	85.06	gold quality
hair follicle	UBERON:0002073	83.16	gold quality
metanephros cortex	UBERON:0010533	83.02	gold quality
pancreas	UBERON:0001264	83.00	gold quality
adult mammalian kidney	UBERON:0000082	79.80	gold quality
body of pancreas	UBERON:0001150	79.37	gold quality
tendon of biceps brachii	UBERON:0008188	77.97	gold quality
vastus lateralis	UBERON:0001379	77.56	gold quality
type B pancreatic cell	CL:0000169	77.46	gold quality
buccal mucosa cell	CL:0002336	77.39	silver quality
nasal cavity epithelium	UBERON:0005384	77.21	gold quality
kidney	UBERON:0002113	77.13	gold quality
pancreatic ductal cell	CL:0002079	76.92	silver quality
tongue squamous epithelium	UBERON:0006919	76.67	gold quality
olfactory bulb	UBERON:0002264	76.54	gold quality
superficial temporal artery	UBERON:0001614	76.01	gold quality
quadriceps femoris	UBERON:0001377	75.99	gold quality
left ventricle myocardium	UBERON:0006566	74.81	gold quality
CA1 field of hippocampus	UBERON:0003881	74.69	gold quality
gall bladder	UBERON:0002110	74.65	gold quality
cardiac muscle of right atrium	UBERON:0003379	74.08	gold quality
biceps brachii	UBERON:0001507	74.04	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	73.33	gold quality
metanephros	UBERON:0000081	73.12	gold quality
Brodmann (1909) area 10	UBERON:0013541	72.53	gold quality
renal medulla	UBERON:0000362	72.51	gold quality
heart right ventricle	UBERON:0002080	72.33	gold quality
cerebellar vermis	UBERON:0004720	72.12	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	72.11	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	1764.03
E-GEOD-131882	yes	1758.12
E-GEOD-81547	yes	590.66
E-GEOD-81608	yes	547.15
E-ENAD-27	yes	523.19
E-MTAB-5061	yes	214.50
E-HCAD-31	yes	20.63
E-GEOD-83139	yes	12.83
E-ANND-3	yes	6.48
E-MTAB-6142	no	3.84

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BRCA1, E2F1, GCM2, JDP2, PITX2, SMARCA5, TCF3, TTF1, VDR

miRNA regulators (miRDB)

102 targeting CASR, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759

Literature-anchored findings (GeneRIF, showing 40)

• acceptor splice site mutation in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism (PMID:11668634)
• A heterozygous missense mutation in exon 6 that substitutes a glutamic acid for the glycine at codon 557 (Gly557Glu), which corresponds to the extracellular domain cosegregates with hypocalciuric hypercalcemia (PMID:11762699)
• gene polymorphism affects the arathyroid response to moderate hypercalcemic suppression in end-stage renal disease (PMID:11863123)
• examinations confirmed the diagnosis of familial hypocalciuric hypercalcemia as a result of C562Y calcium-sensing receptor mutation (PMID:11889154)
• alter the function of the CASR in several different ways. (PMID:11889203)
• role in parallel activation of phosphatidylinositol 4-kinase and phospholipase C (PMID:11907035)
• maintains Ca homeostasis (PMID:11979955)
• role of functional VDREs in CASR gene in mechanism whereby 1,25(OH)2D up-regulates parathyroid, thyroid C-cell, and kidney CASR expression (PMID:12036954)
• A family of autosomal dominant hypocalcemia with a positive correlation between serum calcium and magnesium: a novel gain of function mutation (Ser(820)Phe) in the calcium-sensing receptor. (PMID:12050233)
• Three adjacent serines in the extracellular domains of the CaR are required for L-amino acid-mediated potentiation of receptor function. (PMID:12095982)
• Influence of calcium-sensing receptor gene on urinary calcium excretion in stone-forming patients. (PMID:12239240)
• The amino acid residues critical to both functions of CaR may contribute to interactions with either G proteins or between CaR monomers within the functional dimer (PMID:12399473)
• Protein kinase C phosphorylation of the CaR prevents G protein subtypes from interacting with the region of the receptor critical for releasing Ca(2+) stores (PMID:12409307)
• Data first document the fact that the myeloma cell lines, U266, IM-9, and RPMI8226, all express the calcium-sensing receptor (CaR) protein and mRNA. (PMID:12459170)
• role of R648 stop mutation in familial hypocalciuric hypercalcemia (PMID:12469911)
• functions in human colon carcinomas: promotes E-cadherin expression and suppresses beta-catenin/TCF activation (PMID:12517779)
• protein kinase a and protein kinase c synergize in inhibiting Ca 2+o -stimulated inositol-1,4,5-trisphosphate signaling in calcium-sensing receptor-transfected HEK293 cells (PMID:12605346)
• marked decreases in vitamin D receptor and calcium-sensing receptor expression could be responsible for the high proliferation of parathyroid cells and the pathological progression of hyperparathyroidism (PMID:12656660)
• The calcium-sensing receptor is widely expressed in various tissues and likely serves important cellular functions beyond that of maintaining systemic calcium homeostasis, as evidenced in this review. (PMID:12700051)
• Our data do not support a role of A986S CaR polymorphism in BMD and in the prevalence of fragility fractures in Italian postmenopausal women. (PMID:12773131)
• localization of m-calpain within caveolae may contribute to maintenance of the enzyme in an inactive state and that m-calpain may also contribute to the regulation of calcium-sensing receptor levels. (PMID:12783889)
• new insights into the mechanism of receptor activation and into the mechanism of action of allosteric modulators of the receptor [review] (PMID:12890593)
• Neoplastic colon epithelial cells can respond to antimitogenic signals generated by activation of the CaR as long as they express sufficient amounts of the CaR protein. (PMID:12899245)
• Casr polymorphism does not predict serum calcium level, bone density, calcaneal ultrasound indices, or fracture rate in a large cohort of elderly women. (PMID:14508624)
• model of the transmembrane domain of the human calcium sensing receptor and localization of an allosteric binding site (PMID:14660633)
• patients studied had serological evidence of organ-specific autoimmunity against the CaSR protein in hypoparathyroidism (PMID:14713274)
• CaR dimerization through its ECD is essential for the formation of a functional tertiary structure of the CaR. (PMID:14729680)
• transmembrane segments and amino acid residues involved in the recognition of calcimimetics and calcilytics are delineated (PMID:14976203)
• genotype phenotype analysis in familial isolated hyperparathyroidism (PMID:14985373)
• CaR mutations show reduced pH(o) modulation, suggesting a molecular mechanism for increased calcium-sensing receptor activity at physiological pH(o) (PMID:15201280)
• Proximal and distal signal transduction cascades activated by the calcium sensing receptor may reflect transactivation of the epidermal growth factor receptor by the extracellular calcium-sensing receptor (PMID:15219850)
• Direct sequence analysis of exon 4 of her CASR gene identified a heterozygous R227Q mutation in the extracellular domain of the receptor in familial (benign) hypocalciuric hypercalcemia or neonatal yperparathyroidism. (PMID:15572418)
• the Venus Fly Trap (VFT) domain of CaR, but none of its other major domains, is required for amino acid sensing (PMID:15579475)
• a seven-transmembrane domain region of the human Ca2+ receptor is critical for response to Ca2+ (PMID:15591042)
• Because the activation of CaSR by oral calcium and peptones directly induces gastrin release, the higher gastrin responses to these stimuli suggest an increased sensitivity of gastrin-secreting cells CaSR in patients with hypercalciuria (PMID:15613438)
• CASR responsiveness in parathyroid glands is regulated by G protein receptor kinases and beta-arrestins. (PMID:15637145)
• Interaction with filamin A increases cellular CaR by preventing CaR degradation, thereby facilitating CaR signaling. (PMID:15657061)
• Data show that the calcium-sensing receptor (CASR) gene has several functional kappaB elements that mediate its upregulation by proinflammatory cytokines. (PMID:15684428)
• first report of calcium-sensing receptor (CaSR) being expressed in human adipocytes and adipocyte progenitor cells (PMID:15718278)
• CaR stimulates apoptosis via a pathway involving GTP binding protein alpha subunit (Galpha(i))-dependent ceramide accumulation, activation of stress-activated protein kinase/c-Jun N-terminal kinase, c-Jun phosphorylation & caspase-3, & DNA cleavage. (PMID:15805541)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	casr	ENSDARG00000013649
mus_musculus	Casr	ENSMUSG00000051980
rattus_norvegicus	Casr	ENSRNOG00000002265

Paralogs (4): TAS1R3 (ENSG00000169962), GPRC6A (ENSG00000173612), TAS1R1 (ENSG00000173662), TAS1R2 (ENSG00000179002)

Protein

Protein identifiers

Extracellular calcium-sensing receptor — P41180 (reviewed: P41180)

Alternative names: Parathyroid cell calcium-sensing receptor 1

All UniProt accessions (2): A0A1X7SBX3, P41180

UniProt curated annotations — full annotation on UniProt →

Function. G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis. Senses fluctuations in the circulating calcium concentration: activated by elevated circulating calcium, leading to decreased parathyroid hormone (PTH) secretion in parathyroid glands. In kidneys, acts as a key regulator of renal tubular calcium resorption. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G-proteins) and modulates the activity of downstream effectors. CASR is coupled with different G(q)/G(11), G(i)/G(o)- or G(s)-classes of G-proteins depending on the context. In the parathyroid and kidney, CASR signals through G(q)/G(11) and G(i)/G(o) G-proteins: G(q)/G(11) coupling activates phospholipase C-beta, releasing diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) second messengers, while G(i)/G(o) coupling mediates inhibition of adenylate cyclase activity. The G-protein-coupled receptor activity is activated by a co-agonist mechanism: aromatic amino acids, such as Trp or Phe, act concertedly with divalent cations, such as calcium or magnesium, to achieve full receptor activation. Acts as an activator of the NLRP3 inflammasome via G(i)/G(o)-mediated signaling: down-regulation of cyclic AMP (cAMP) relieving NLRP3 inhibition by cAMP. Acts as a regulator of proton-sensing receptor GPR68 in a seesaw manner: CASR-mediated signaling inhibits GPR68 signaling in response to extracellular calcium, while GPR68 inhibits CASR in presence of extracellular protons.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with VCP. Interacts with ARRB1.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in the temporal lobe, frontal lobe, parietal lobe, hippocampus, and cerebellum. Also found in kidney, lung, liver, heart, skeletal muscle, placenta.

Post-translational modifications. Phosphorylation at Thr-888 by PKC impairs coupling with G(q)/G(11) G-proteins, while it does not affect G(i)/G(o)-coupling. Phosphorylation at Ser-892 by PKC and Ser-899 by PKA promote plasma membrane localization. Ubiquitinated by RNF19A; which induces proteasomal degradation. N-glycosylated.

Disease relevance. Hypocalciuric hypercalcemia, familial 1 (HHC1) [MIM:145980] A form of hypocalciuric hypercalcemia, a disorder of mineral homeostasis that is transmitted as an autosomal dominant trait with a high degree of penetrance. It is characterized biochemically by lifelong elevation of serum calcium concentrations and is associated with inappropriately low urinary calcium excretion and a normal or mildly elevated circulating parathyroid hormone level. Hypermagnesemia is typically present. Affected individuals are usually asymptomatic and the disorder is considered benign. However, chondrocalcinosis and pancreatitis occur in some adults. The disease is caused by variants affecting the gene represented in this entry. Hyperparathyroidism, neonatal severe (NSHPT) [MIM:239200] A disorder characterized by severe hypercalcemia, bone demineralization, and failure to thrive usually manifesting in the first 6 months of life. If untreated, NSHPT can be a devastating neurodevelopmental disorder, which in some cases is lethal without parathyroidectomy. The disease is caused by variants affecting the gene represented in this entry. Hypocalcemia, autosomal dominant 1 (HYPOC1) [MIM:601198] A disorder of mineral homeostasis characterized by blood calcium levels below normal, and low or normal serum parathyroid hormone concentrations. Disease manifestations include mild or asymptomatic hypocalcemia, paresthesias, carpopedal spasm, seizures, hypercalciuria with nephrocalcinosis or kidney stones, and ectopic and basal ganglia calcifications. Few patients manifest hypocalcemia and features of Bartter syndrome, including hypomagnesemia, hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronemia. The disease is caused by variants affecting the gene represented in this entry. Epilepsy, idiopathic generalized 8 (EIG8) [MIM:612899] A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Seizure types are variable, but include myoclonic seizures, absence seizures, febrile seizures, complex partial seizures, and generalized tonic-clonic seizures. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. In resting state, adopts an open conformation, anion-binding promoting the inactive configuration. Upon aromatic amino acid-binding, the groove in the extracellular venus flytrap module is closed, thereby inducing the formation of a novel homodimer interface between subunits. Calcium ions stabilize the active state by enhancing homodimer interactions between membrane-proximal domains to fully activate the receptor. Upon activation, the homodimer adopts an asymmetric configuration of the 7-transmembrane region that primes one protomer for G-protein coupling. G-protein binding expands the transmembrane dimer interface; the restriction imposed by the receptor dimer, in combination with intracellular loop 2 (ICL2), enables G-protein activation by facilitating conformational transition of G-protein alpha. Coupling to different classes of G-proteins results in distinct CASR-G-protein interfaces. Activated by glucose, which acts as a positive allosteric modulator. Activated by positive allosteric modulator drugs cinacalcet, evocalcet and etelcalcetide, which are clinically used for the treatment of hyperparathyroidism and familial hypocalciuric hypercalcemia. Inhibited by NPS-2143, a negative allosteric modulator tested for the treatment of hypocalcemia. Activated by velcalcetide (AMG 416), a D-amino acid-containing peptide agonist that is being evaluated for the treatment of secondary hyperparathyroidism in chronic kidney disease patients receiving hemodialysis. Velcalcetide agonist acts by forming a disulfide bond with Cys-482.

Domain organisation. The extracellular regions of the homodimer interact in a side-by-side fashion while facing opposite directions. Each extracellular region consists of three domains, LB1 (ligand-binding 1), LB2 and CR (cysteine-rich). The two lobe-shaped domains LB1 and LB2 form a venus flytrap module. In the inactive configuration, the venus flytrap modules of both protomers are in the open conformation associated with the resting state (open-open) and the interdomain cleft is empty. In addition, each protomer contains three anions, which reinforce the inactive conformation, and one calcium ion. In the active configuration, both protomers of extracellular regions have the closed conformation associated with agonist-binding (closed-closed). The ligand-binding cleft of each protomer is solely occupied by an aromatic amino-acid. Calcium is bound at four novel sites, including one at the homodimer interface. Agonist-binding induces large conformational changes within the extracellular region homodimer: first, the venus flytrap module of each protomer undergoes domain closure. Second, the LB2 regions of the two protomers approach each other, resulting in an expansion of the homodimer interactions involving LB2 domains. Third, the CR regions of the two subunits interact to form a large homodimer interface that is unique to the active state. The CR regions are brought into close contact by the motion involving LB2 since the two domains are rigidly associated within each subunit. G-protein recognition is mediated by the intracellular loop 2 (ICL2) and the C-terminus, which contribute differentially towards the binding of the 2 G-protein subtypes G(q)/G(11) and G(i)/G(o), resulting in distinct CASR-G-protein interfaces. The C-terminus confers selectivity for G(q)/G(11), while it contributes less to G(i)/G(o)-coupling. The C-terminus adopts opposing orientations for G(q)/G(11) and G(i)/G(o)-coupling. The arginine-rich retention motif inhibits localization to the plasma membrane, possibly by promoting interaction with 14-3-3 proteins. Phosphorylation at Ser-892 by PKC and Ser-899 by PKA relieve inhibition and promote plasma membrane localization.

Similarity. Belongs to the G-protein coupled receptor 3 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P41180-1	1	yes
P41180-2	2

RefSeq proteins (2): NP_000379, NP_001171536 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000068	GPCR_3_Ca_sens_rcpt-rel	Family
IPR000337	GPCR_3	Family
IPR001828	ANF_lig-bd_rcpt	Domain
IPR011500	GPCR_3_9-Cys_dom	Domain
IPR017978	GPCR_3_C	Domain
IPR017979	GPCR_3_CS	Conserved_site
IPR028082	Peripla_BP_I	Homologous_superfamily
IPR038550	GPCR_3_9-Cys_sf	Homologous_superfamily

Pfam: PF00003, PF01094, PF07562

UniProt features (361 total): sequence variant 124, mutagenesis site 58, strand 43, helix 39, binding site 22, region of interest 12, turn 12, glycosylation site 11, disulfide bond 10, topological domain 8, transmembrane region 7, modified residue 5, sequence conflict 3, compositionally biased region 3, signal peptide 1, chain 1, site 1, splice variant 1

Structure

Experimental structures (PDB)

31 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5FBK	X-RAY DIFFRACTION	2.1
7M3G	ELECTRON MICROSCOPY	2.5
5K5S	X-RAY DIFFRACTION	2.6
5FBH	X-RAY DIFFRACTION	2.7
7SIL	ELECTRON MICROSCOPY	2.7
7SIM	ELECTRON MICROSCOPY	2.7
8WPG	ELECTRON MICROSCOPY	2.7
7M3F	ELECTRON MICROSCOPY	2.8
8SZF	ELECTRON MICROSCOPY	2.8
9C1P	ELECTRON MICROSCOPY	2.8
9C2F	ELECTRON MICROSCOPY	2.8
7E6T	ELECTRON MICROSCOPY	3
5K5T	X-RAY DIFFRACTION	3.1
8SZH	ELECTRON MICROSCOPY	3.1
8WPU	ELECTRON MICROSCOPY	3.1
7M3E	ELECTRON MICROSCOPY	3.2
9ASB	ELECTRON MICROSCOPY	3.4
7DTV	ELECTRON MICROSCOPY	3.5
8SZI	ELECTRON MICROSCOPY	3.5
9AXF	ELECTRON MICROSCOPY	3.5
9J7I	ELECTRON MICROSCOPY	3.55
8SZG	ELECTRON MICROSCOPY	3.6
9AVG	ELECTRON MICROSCOPY	3.6
9AYF	ELECTRON MICROSCOPY	3.6
7DTT	ELECTRON MICROSCOPY	3.8
9AVL	ELECTRON MICROSCOPY	3.8
7M3J	ELECTRON MICROSCOPY	4.1
7DTU	ELECTRON MICROSCOPY	4.4
7DTW	ELECTRON MICROSCOPY	4.5
7SIN	ELECTRON MICROSCOPY	5.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41180-F1	76.01	0.43

Antibody-complex structures (SAbDab): 4 — 7E6U, 8WPU, 9AXF, 9AYF

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 482 (important for ability of agonist amg 416 to activate g-protein-coupled receptor activity)

Ligand- & substrate-binding residues (22): 66–70; 81; 84; 87; 88; 100; 145; 147; 168; 170; 170; 188 …

Post-translational modifications (5): 888, 892, 899, 920, 1061

Disulfide bonds (10): 60–101, 129, 131, 236–561, 358–395, 437–449, 542–562, 546–565, 568–582, 585–598

Glycosylation sites (11): 90, 130, 261, 287, 386, 400, 446, 468, 488, 541, 594

Mutagenesis-validated functional residues (58):

Position	Phenotype
29	increased calcium sensitivity.
29	does not affect calcium sensitivity.
51	decreased calcium-induced g-protein-coupled receptor activity.
69	abolishes g-protein coupled receptor signaling pathway.
70	abolished calcium-induced g-protein-coupled receptor activity.
102	abolishes g-protein coupled receptor activity.
145	abolished calcium-induced g-protein-coupled receptor activity.
145	reduced calcium-induced g-protein-coupled receptor activity.
147	abolished calcium-induced g-protein-coupled receptor activity.
170	abolished calcium-induced g-protein-coupled receptor activity.
170	reduced calcium-induced g-protein-coupled receptor activity.
190	reduced calcium-induced g-protein-coupled receptor activity.
193	reduced calcium-induced g-protein-coupled receptor activity.
216	strongly reduced calcium-induced g-protein-coupled receptor activity.
218	abolished calcium-induced g-protein-coupled receptor activity.
272	does not affect calcium-induced g-protein-coupled receptor activity.
275	does not affect calcium-induced g-protein-coupled receptor activity.
297	abolished calcium-induced g-protein-coupled receptor activity.
297	abolishes ability to sense calcium or magnesium levels.
417	abolishes g-protein coupled receptor signaling pathway.
444	decreased calcium-induced g-protein-coupled receptor activity.
458	decreased calcium-induced g-protein-coupled receptor activity.
482	abolishes ability of agonist amg 416 to activate g-protein-coupled receptor activity.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-416476	G alpha (q) signalling events
R-HSA-418594	G alpha (i) signalling events
R-HSA-420499	Class C/3 (Metabotropic glutamate/pheromone receptors)
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 472 (showing top): GOBP_CELLULAR_RESPONSE_TO_LIPOPROTEIN_PARTICLE_STIMULUS, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_ACID_SECRETION, GOBP_BEHAVIOR, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_INFLAMMATORY_RESPONSE, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_INSULIN_SECRETION, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION

GO Biological Process (37): ossification (GO:0001503), response to ischemia (GO:0002931), detection of calcium ion (GO:0005513), intracellular calcium ion homeostasis (GO:0006874), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), JNK cascade (GO:0007254), chemosensory behavior (GO:0007635), positive regulation of cell population proliferation (GO:0008284), anatomical structure morphogenesis (GO:0009653), positive regulation of gene expression (GO:0010628), positive regulation of insulin secretion (GO:0032024), bile acid secretion (GO:0032782), cellular response to hepatocyte growth factor stimulus (GO:0035729), vasodilation (GO:0042311), positive regulation of vasoconstriction (GO:0045907), branching morphogenesis of an epithelial tube (GO:0048754), positive regulation of positive chemotaxis (GO:0050927), regulation of calcium ion transport (GO:0051924), fat pad development (GO:0060613), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to vitamin D (GO:0071305), cellular response to glucose stimulus (GO:0071333), cellular response to low-density lipoprotein particle stimulus (GO:0071404), cellular response to hypoxia (GO:0071456), response to fibroblast growth factor (GO:0071774), positive regulation of calcium ion import (GO:0090280), regulation of presynaptic membrane potential (GO:0099505), positive regulation of NLRP3 inflammasome complex assembly (GO:1900227), cellular response to peptide (GO:1901653), chloride transmembrane transport (GO:1902476), signal transduction (GO:0007165), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), response to metal ion (GO:0010038), response to calcium ion (GO:0051592), adenylate cyclase-activating G protein-coupled cAMP receptor signaling pathway (GO:0140582)

GO Molecular Function (10): G protein-coupled receptor activity (GO:0004930), integrin binding (GO:0005178), calcium ion binding (GO:0005509), amino acid binding (GO:0016597), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), transmembrane transporter binding (GO:0044325), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (10): plasma membrane (GO:0005886), cell surface (GO:0009986), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), presynaptic membrane (GO:0042734), neuronal cell body (GO:0043025), axon terminus (GO:0043679), glutamatergic synapse (GO:0098978), membrane (GO:0016020), axon (GO:0030424)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
GPCR downstream signalling	2
Signaling by GPCR	2
GPCR ligand binding	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	2
binding	2
protein binding	2
cellular anatomical structure	2
plasma membrane region	2
presynapse	2
multicellular organismal process	1
response to stress	1
detection of chemical stimulus	1
response to calcium ion	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
G protein-coupled receptor activity	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
phospholipase C activator activity	1
MAPK cascade	1
behavior	1
response to chemical	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
developmental process	1
anatomical structure development	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
monocarboxylic acid transport	1
acid secretion	1
response to hepatocyte growth factor	1
cellular response to growth factor stimulus	1
blood vessel diameter maintenance	1
regulation of vasoconstriction	1
vasoconstriction	1
positive regulation of multicellular organismal process	1

Protein interactions and networks

STRING

2643 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASR	PTH	P01270	950
CASR	GCM2	O75603	943
CASR	KCNJ1	P48048	860
CASR	CDC73	Q6P1J9	856
CASR	GNA11	P29992	783
CASR	MEN1	O00255	772
CASR	SLC12A1	Q13621	753
CASR	FLNA	P21333	751
CASR	PTHLH	P12272	744
CASR	GABBR1	Q9UBS5	737
CASR	AP2S1	P53680	728
CASR	FGF23	Q9GZV9	720
CASR	GNAQ	P50148	702
CASR	RAMP1	O60894	696
CASR	TRPV5	Q9NQA5	666
CASR	CLDN14	O95500	666

IntAct

4 interactions, top by confidence:

A	B	Type	Score
TMED2	CASR	psi-mi:“MI:0915”(physical association)	0.510
CASR	TMED2	psi-mi:“MI:0915”(physical association)	0.510

BioGRID (45): CASR (Two-hybrid), Os9 (Two-hybrid), CASR (Affinity Capture-Western), OS9 (Affinity Capture-Western), NFKBIA (Two-hybrid), NFKBIA (Affinity Capture-Western), CASR (Affinity Capture-Western), HIF1A (Affinity Capture-Western), CASR (Affinity Capture-Western), CASR (Affinity Capture-Western), HIF1A (Affinity Capture-Western), CASR (Affinity Capture-Western), VHL (Affinity Capture-Western), CASR (Affinity Capture-Western), VHL (Reconstituted Complex)

ESM2 similar proteins: A0A0G2K1Q8, A3QNZ8, A3QNZ9, A3QP00, A3QP01, A3QP07, A3QP08, A3QP09, D4A3T6, E1BPQ3, E9Q4J9, E9Q6I0, G5ECB2, O35659, O62714, O70410, O75899, O88871, P32082, P35384, P41180, P43220, P48442, P48960, Q49HI0, Q58Y75, Q5T6X5, Q5U9X3, Q61606, Q6TAC4, Q70VB1, Q717C1, Q7RTX1, Q80T41, Q8BG22, Q8K385, Q8K4Z6, Q8R420, Q8SQA4, Q8TE23

Diamond homologs: A3QNZ8, A3QNZ9, A3QP00, A3QP01, A3QP07, A3QP08, A3QP09, O62714, P35384, P41180, P48442, Q49HI0, Q7RTX1, Q8TE23, Q923K1, Q925I4, Q99PG6, Q9PW88, Q9QY96, Q9Z0R7, Q9Z0R8, Q49HH9, Q49KI5, E1BPQ3, Q5T6X5, Q5U9X3, Q70VB1, Q8K4Z6, E9Q6I0, O70410, Q6TAC4, O00222, O15303, P23385, P31421, P31422, P31423, P31424, P35349, P35400

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PRKCA	down-regulates	CASR	phosphorylation
PRKCB	“down-regulates activity”	CASR	phosphorylation
GCM2	“up-regulates quantity by expression”	CASR	“transcriptional regulation”
RNF19A	“down-regulates quantity by destabilization”	CASR	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

3104 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	186
Likely pathogenic	97
Uncertain significance	1583
Likely benign	961
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1066835	NM_000388.4(CASR):c.2415del (p.Lys805fs)	Pathogenic
1068041	NM_000388.4(CASR):c.2254del (p.Arg752fs)	Pathogenic
1068215	NM_000388.4(CASR):c.1376A>G (p.Gln459Arg)	Pathogenic
1068229	NM_000388.4(CASR):c.2297_2298dup (p.Glu767fs)	Pathogenic
1070118	NM_000388.4(CASR):c.1081C>T (p.Gln361Ter)	Pathogenic
1071373	NC_000003.11:g.(?121973037)(122004038_?)del	Pathogenic
1071398	NM_000388.4(CASR):c.1783del (p.His595fs)	Pathogenic
1071747	NM_000388.4(CASR):c.1056G>A (p.Trp352Ter)	Pathogenic
1074500	NM_000388.4(CASR):c.924_925dup (p.Gln309fs)	Pathogenic
1074918	NM_000388.4(CASR):c.1054del (p.Trp352fs)	Pathogenic
1074921	NM_000388.4(CASR):c.1773_1774del (p.Ser591_Asn592insTer)	Pathogenic
1075778	NM_000388.4(CASR):c.547_548del (p.Phe183fs)	Pathogenic
1076659	NM_000388.4(CASR):c.1868del (p.Gly623fs)	Pathogenic
1177515	NM_000388.4(CASR):c.209G>A (p.Trp70Ter)	Pathogenic
1256482	NM_000388.4(CASR):c.2154G>A (p.Trp718Ter)	Pathogenic
1328470	NM_000388.4(CASR):c.1589G>A (p.Trp530Ter)	Pathogenic
1361655	NM_000388.4(CASR):c.186-2A>G	Pathogenic
1373420	NM_000388.4(CASR):c.1759dup (p.Asp587fs)	Pathogenic
1376400	NM_000388.4(CASR):c.1557_1560del (p.Glu519fs)	Pathogenic
1377560	NM_000388.4(CASR):c.2030del (p.Cys677fs)	Pathogenic
1378885	NM_000388.4(CASR):c.528del (p.Asn176fs)	Pathogenic
1408979	NM_000388.4(CASR):c.2533_2545del (p.Ser845fs)	Pathogenic
1425273	NM_000388.4(CASR):c.1802del (p.Lys601fs)	Pathogenic
1432045	NM_000388.4(CASR):c.961_962del (p.Ala321fs)	Pathogenic
1442327	NM_000388.4(CASR):c.2148dup (p.Lys717fs)	Pathogenic
1449397	NM_000388.4(CASR):c.1852del (p.Leu618fs)	Pathogenic
1451604	NM_000388.4(CASR):c.349C>T (p.Gln117Ter)	Pathogenic
1453597	NM_000388.4(CASR):c.1542T>G (p.Tyr514Ter)	Pathogenic
1453750	NM_000388.4(CASR):c.357_358del (p.Lys119fs)	Pathogenic
1454775	NM_000388.4(CASR):c.384C>G (p.Phe128Leu)	Pathogenic

SpliceAI

1593 predictions. Top by Δscore:

Variant	Effect	Δscore
3:122183813:G:GG	donor_gain	0.9900
3:122253947:GAA:G	acceptor_gain	0.9900
3:122275806:CTTTA:C	acceptor_loss	0.9900
3:122275808:TTA:T	acceptor_loss	0.9900
3:122275809:TAG:T	acceptor_loss	0.9900
3:122275810:A:AG	acceptor_gain	0.9900
3:122275811:G:GG	acceptor_gain	0.9900
3:122275953:G:GT	donor_gain	0.9900
3:122276038:GGGAG:G	donor_gain	0.9900
3:122276039:GGAGG:G	donor_gain	0.9900
3:122276040:G:T	donor_gain	0.9900
3:122276043:G:GA	donor_loss	0.9900
3:122276044:TA:T	donor_loss	0.9900
3:122282107:CTCCA:C	acceptor_loss	0.9900
3:122282108:TCCA:T	acceptor_loss	0.9900
3:122282110:CAGGT:C	acceptor_loss	0.9900
3:122282111:AGG:A	acceptor_loss	0.9900
3:122282112:G:GC	acceptor_loss	0.9900
3:122282217:G:T	donor_gain	0.9900
3:122282232:GACAG:G	donor_gain	0.9900
3:122282233:ACAGG:A	donor_loss	0.9900
3:122282234:CAG:C	donor_loss	0.9900
3:122282235:AG:A	donor_loss	0.9900
3:122282236:GG:G	donor_loss	0.9900
3:122282237:G:T	donor_loss	0.9900
3:122282238:T:G	donor_loss	0.9900
3:122283685:A:AG	acceptor_gain	0.9900
3:122283686:G:GG	acceptor_gain	0.9900
3:122183811:GA:G	donor_gain	0.9800
3:122253946:A:AG	acceptor_gain	0.9800

AlphaMissense

7146 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:122257190:G:C	D99H	1.000
3:122257191:A:T	D99V	1.000
3:122257197:G:A	C101Y	1.000
3:122257197:G:T	C101F	1.000
3:122257198:C:G	C101W	1.000
3:122261531:A:C	S166R	1.000
3:122261533:T:A	S166R	1.000
3:122261533:T:G	S166R	1.000
3:122261589:G:C	R185P	1.000
3:122261651:T:A	W206R	1.000
3:122261651:T:C	W206R	1.000
3:122261690:G:T	G219W	1.000
3:122261741:T:A	C236S	1.000
3:122261742:G:C	C236S	1.000
3:122282128:T:A	C542S	1.000
3:122282129:G:C	C542S	1.000
3:122282140:T:A	C546S	1.000
3:122282141:G:C	C546S	1.000
3:122282188:T:A	C562S	1.000
3:122282189:G:C	C562S	1.000
3:122282191:T:C	F563L	1.000
3:122282193:T:A	F563L	1.000
3:122282193:T:G	F563L	1.000
3:122282197:T:A	C565S	1.000
3:122282198:G:C	C565S	1.000
3:122282206:T:A	C568S	1.000
3:122282207:G:C	C568S	1.000
3:122283698:T:A	C582S	1.000
3:122283699:G:C	C582S	1.000
3:122283746:T:A	C598S	1.000

dbSNP variants (sampled 300 via entrez): RS1000003685 (3:122205231 A>G), RS1000037989 (3:122291985 C>A,T), RS1000060139 (3:122202959 C>A), RS1000079803 (3:122227811 A>G), RS1000096897 (3:122206531 A>G), RS1000140191 (3:122248012 A>G), RS1000143904 (3:122265971 G>A,C), RS1000188964 (3:122223674 C>T), RS1000212593 (3:122265806 A>G), RS1000231870 (3:122235283 G>A,C,T), RS1000251383 (3:122225090 A>G), RS1000320472 (3:122186570 C>T), RS1000339195 (3:122269047 G>A,T), RS1000342365 (3:122229051 C>A,T), RS1000430468 (3:122193586 T>C)

Disease associations

OMIM: gene MIM:601199 | disease phenotypes: MIM:601198, MIM:145980, MIM:239200, MIM:612899, MIM:146200, MIM:607364, MIM:600669, MIM:263800, MIM:601678

GenCC curated gene-disease

Disease	Classification	Inheritance
familial hypocalciuric hypercalcemia 1	Definitive	Autosomal dominant
autosomal dominant hypocalcemia 1	Definitive	Autosomal dominant
neonatal severe primary hyperparathyroidism	Strong	Autosomal dominant
autosomal dominant hypocalcemia	Supportive	Autosomal dominant
epilepsy, idiopathic generalized, susceptibility to, 8	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (4)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
neonatal severe primary hyperparathyroidism	Definitive	AR
familial hypocalciuric hypercalcemia 1	Definitive	AD
epilepsy	Refuted	AD
autosomal dominant hypocalcemia 1	Definitive	AD

Mondo (20): autosomal dominant hypocalcemia 1 (MONDO:0011013), familial hypocalciuric hypercalcemia (MONDO:0018458), familial hypocalciuric hypercalcemia 1 (MONDO:0007791), neonatal severe primary hyperparathyroidism (MONDO:0009397), epilepsy, idiopathic generalized, susceptibility to, 8 (MONDO:0013032), neurodevelopmental disorder (MONDO:0700092), hereditary neoplastic syndrome (MONDO:0015356), hypercalcemia disease (MONDO:0001566), Bartter syndrome with hypocalcemia (MONDO:0016983), autosomal dominant hypocalcemia (MONDO:0018543), prostate cancer (MONDO:0008315), familial hypoparathyroidism (MONDO:0016390), hypertrophic cardiomyopathy (MONDO:0005045), parathyroid gland adenoma (MONDO:0006890), Bartter disease type 3 (MONDO:0011822)

Orphanet (12): Familial hypocalciuric hypercalcemia (Orphanet:405), Neonatal severe primary hyperparathyroidism (Orphanet:417), Familial hypocalciuric hypercalcemia type 1 (Orphanet:93372), Inherited cancer-predisposing syndrome (Orphanet:140162), Autosomal dominant hypocalcemia (Orphanet:428), Familial prostate cancer (Orphanet:1331), Familial isolated hypoparathyroidism (Orphanet:2238), Rare hypertrophic cardiomyopathy (Orphanet:217569), Bartter syndrome (Orphanet:112), Bartter syndrome type 3 (Orphanet:93605), Gitelman syndrome (Orphanet:358), Bartter syndrome with hypocalcemia (Orphanet:263417)

HPO phenotypes

89 total (30 of 89 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000103	Polyuria
HP:0000121	Nephrocalcinosis
HP:0000648	Optic atrophy
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000774	Narrow chest
HP:0000787	Nephrolithiasis
HP:0000819	Diabetes mellitus
HP:0000820	Abnormality of the thyroid gland
HP:0000843	Hyperparathyroidism
HP:0000848	Increased circulating renin concentration
HP:0000944	Abnormal metaphysis morphology
HP:0000952	Jaundice
HP:0000958	Dry skin
HP:0000964	Eczematoid dermatitis
HP:0001231	Abnormal fingernail morphology
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001281	Tetany
HP:0001290	Generalized hypotonia
HP:0001336	Myoclonus
HP:0001508	Failure to thrive
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0001635	Congestive heart failure
HP:0001733	Pancreatitis

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000703_2	Phosphorus levels	4.000000e-09
GCST000736_1	Calcium levels	6.000000e-37
GCST000769_5	Calcium levels	2.000000e-22
GCST001776_14	Cardiac Troponin-T levels	4.000000e-06
GCST002201_1	Calcium levels	9.000000e-86
GCST002857_5	Calcium levels	2.000000e-06
GCST002911_1	Calcium levels	4.000000e-08
GCST003086_4	Kidney stones	2.000000e-08
GCST003540_5	Clinical laboratory measurements	2.000000e-51
GCST003879_5	Serum parathyroid hormone levels	1.000000e-09
GCST005982_13	Calcium levels	1.000000e-38
GCST007847_108	Type 2 diabetes	5.000000e-09
GCST008479_6	Psoriasis	2.000000e-10
GCST009698_106	Metabolite levels	2.000000e-08
GCST010118_24	Type 2 diabetes	3.000000e-09
GCST010919_3	QT interval	4.000000e-08
GCST90002381_184	Eosinophil count	2.000000e-15
GCST90002382_579	Eosinophil percentage of white cells	2.000000e-15
GCST90025872_4	Chronic widespread musculoskeletal pain	3.000000e-06

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004861	phosphorus measurement
EFO:0004838	calcium measurement
EFO:0005043	cardiac troponin T measurement
EFO:0004297	clinical laboratory measurement
EFO:0010118	sphingomyelin measurement
EFO:0004682	QT interval
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0010099	chronic widespread pain

MeSH disease descriptors (12)

Descriptor	Name	Tree numbers
D001477	Bartter Syndrome	C12.050.351.968.419.815.279; C12.200.777.419.815.279; C12.950.419.815.279; C19.053.800.604.249
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D053579	Gitelman Syndrome	C12.050.351.968.419.815.491; C12.200.777.419.815.491; C12.950.419.815.491; C16.320.831.491
D006934	Hypercalcemia	C18.452.174.451; C18.452.950.340
D049950	Hyperparathyroidism, Primary	C19.642.355.239
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D065886	Neurodevelopmental Disorders	F03.625
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C562694	Epilepsy, Idiopathic Generalized (supp.)
C563375	Hyperparathyroidism, Neonatal Severe Primary (supp.)
C537145	Hypocalciuric hypercalcemia, familial, type 1 (supp.)
C537156	Hypoparathyroidism familial isolated (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1878 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

10 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 13,308 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1200776	CINACALCET HYDROCHLORIDE	4	1,220
CHEMBL1201284	CINACALCET	4	5,917
CHEMBL1672973	ENCALERET	3	33
CHEMBL4297621	EVOCALCET	3	39
CHEMBL1084513	SB-423562	2	30
CHEMBL1198855	RONACALERET	2	75
CHEMBL2107572	TECALCET HYDROCHLORIDE	2	100
CHEMBL254832	FENDILINE	2	5,707
CHEMBL292376	TECALCET	2	168
CHEMBL597800	ATF-936	1	19

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1042636	CASR		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Calcium-sensing receptor

Most potent curated ligand interactions (28 total), top 25:

Ligand	Action	Affinity	Parameter
ATF936	Negative	8.9	pIC50
AXT914	Negative	8.85	pIC50
upacicalcet	Positive	8.09	pIC50
encaleret	Negative	7.9	pIC50
(R)-2h [PMID:19625189]	Negative	7.39	pIC50
compound 18c [PMID:19143533]	Negative	7.12	pIC50
SB-423562	Negative	7.1	pIC50
evocalcet	Positive	7.03	pEC50
2-methyl-3-phenethyl-3H-pyrimidin-4-one	Antagonist	7.0	pIC50
compound (S)-3h [PMID: 15686947]	Antagonist	6.9	pIC50
ronacaleret	Negative	6.8	pIC50
nanobody Nb4	Positive	6.7	pEC50
NPS 2143	Negative	6.7	pKB
nanobody NB32	Negative	6.69	pIC50
cinacalcet	Positive	6.6	pKB
tecalcet	Positive	6.5	pKd
AC265347	Positive	6.4	pKB
calhex 231	Negative	6.4	pIC50
calindol	Positive	6.3	pKB
compound 17 [PMID: 15300839]	Antagonist	5.3	pIC50
gosicalcetide	Agonist	5.2	pEC50
etelcalcetide	Positive	4.6	pEC50
L-tryptophan	Positive	4.4	pKd
1-arylmethylpyrrolidin-2-yl ethanol amine	Antagonist	4.3	pIC50
neomycin	Full agonist	4.0	pKd

Binding affinities (BindingDB)

75 measured of 98 human assays (98 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S)-2-amino-3-[(5-chloro-2-hydroxy-3-sulfophenyl)carbamoylamino]propanoic acid	EC50	3 nM	US-9253997: Alkylamine derivative
2-amino-3-[(3-chloro-2-methyl-5-sulfophenyl)carbamoylamino]propanoic acid	EC50	3 nM	US-9253997: Alkylamine derivative
3-[[(2S)-2-amino-3-methoxy-3-oxopropyl]carbamoylamino]-5-chloro-2-hydroxybenzenesulfonic acid	EC50	3 nM	US-9253997: Alkylamine derivative
(2S)-2-amino-3-[(3-chloro-2-methyl-5-sulfophenyl)carbamothioylamino]propanoic acid	EC50	4 nM	US-9253997: Alkylamine derivative
N-(1-Adamantyl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrimidine-3-carboxamide	IC50	10 nM
(2S)-2-amino-3-[(3-sulfophenyl)carbamoylamino]propanoic acid	EC50	18 nM	US-9253997: Alkylamine derivative
3-[[(4S)-4-amino-5-(hydroxyamino)-5-oxopentanoyl]amino]-5-chloro-2-hydroxybenzenesulfonic acid	EC50	39 nM	US-9253997: Alkylamine derivative
(2R)-2-amino-3-[(3-sulfophenyl)carbamoylsulfanyl]propanoic acid	EC50	40 nM	US-9253997: Alkylamine derivative
N-(1-Adamantyl)-5-phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo-[1,5-a]pyrimidine-3-carboxamide	IC50	40 nM
6-[(2H-1,3-benzodioxol-5-ylmethyl)amino]-2-(2,6-dimethoxypyridin-3-yl)-N-(2-phenoxyethyl)pyridine-3-carboxamide	IC50	60 nM
2-{[(3-chlorophenyl)methyl]amino}-N-(2-phenoxyethyl)-4-(3,4,5-trimethoxyphenyl)pyrimidine-5-carboxamide	IC50	70 nM
6-{[(2S)-1-hydroxy-3-phenylpropan-2-yl]amino}-N-(2-phenoxyethyl)-2-(3,4,5-trimethoxyphenyl)pyridine-3-carboxamide	IC50	76 nM
N-(1-Adamantyl)-7-methyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr-imidine-3-carboxamide	IC50	76 nM
1-Adamantyl-5-phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo-[1,5-a]-pyrimidine-3-carboxylate	IC50	97 nM
N-(1-Adamantyl)-5-(2-chlorophenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	110 nM
6-[(2H-1,3-benzodioxol-5-ylmethyl)amino]-N-(2-phenoxyethyl)-2-(3,4,5-trimethoxyphenyl)pyridine-3-carboxamide	IC50	130 nM
2-(2,6-dimethoxypyridin-3-yl)-6-{[(2S)-1-hydroxy-3-phenylpropan-2-yl]amino}-N-(2-phenoxyethyl)pyridine-3-carboxamide	IC50	140 nM
2-[(2H-1,3-benzodioxol-5-ylmethyl)amino]-N-(2-phenoxyethyl)-4-(3,4,5-trimethoxyphenyl)pyrimidine-5-carboxamide	IC50	150 nM
2-{[(2S)-1-hydroxy-3-phenylpropan-2-yl]amino}-N-(2-phenoxyethyl)-4-(3,4,5-trimethoxyphenyl)pyrimidine-5-carboxamide	IC50	150 nM
2-[(2H-1,3-benzodioxol-5-ylmethyl)amino]-N-[1-(4-chlorophenyl)propan-2-yl]-4-(2,6-dimethoxypyridin-3-yl)pyrimidine-5-carboxamide	IC50	150 nM
6-[benzyl(ethyl)amino]-N-(2-phenoxyethyl)-2-(3,4,5-trimethoxyphenyl)pyridine-3-carboxamide	IC50	154 nM
6-{[(3-chlorophenyl)methyl]amino}-N-(2-phenoxyethyl)-2-(3,4,5-trimethoxyphenyl)pyridine-3-carboxamide	IC50	162 nM
3-[[(4S)-4-amino-4-(5-methyl-1,3,4-oxadiazol-2-yl)butanoyl]amino]-5-chloro-2-hydroxybenzenesulfonic acid	EC50	180 nM	US-9253997: Alkylamine derivative
6-{[(3-chlorophenyl)methyl]amino}-2-(2,6-dimethoxypyridin-3-yl)-N-(2-phenoxyethyl)pyridine-3-carboxamide	IC50	197 nM
2-[benzyl(ethyl)amino]-N-(2-phenoxyethyl)-4-(3,4,5-trimethoxyphenyl)pyrimidine-5-carboxamide	IC50	200 nM
2-[(2H-1,3-benzodioxol-5-ylmethyl)amino]-4-(2,6-dimethoxypyridin-3-yl)-N-(2-phenoxyethyl)pyrimidine-5-carboxamide	IC50	220 nM
3-[[(4S)-4-amino-5-oxo-5-[2-(2-phenylacetyl)hydrazinyl]pentanoyl]amino]-5-chloro-2-hydroxybenzenesulfonic acid	EC50	250 nM	US-9253997: Alkylamine derivative
(2S)-3-[(3-chloro-4-methyl-5-sulfophenyl)carbamoylamino]-2-(methylamino)propanoic acid	EC50	313 nM	US-9253997: Alkylamine derivative
N-(1-Adamantyl)-5-(3-chlorophenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	320 nM
2-{[(3-methoxyphenyl)methyl]amino}-N-(2-phenoxyethyl)-4-(3,4,5-trimethoxyphenyl)pyrimidine-5-carboxamide	IC50	340 nM
2-{[2-(2-methoxyphenyl)ethyl]amino}-N-(2-phenoxyethyl)-4-(3,4,5-trimethoxyphenyl)pyrimidine-5-carboxamide	IC50	340 nM
2-[benzyl(ethyl)amino]-4-(2,6-dimethoxypyridin-3-yl)-N-(2-phenoxyethyl)pyrimidine-5-carboxamide	IC50	360 nM
N-(2H-1,3-benzodioxol-5-ylmethyl)-4-(2,6-dimethoxypyridin-3-yl)-5-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyl)pyrimidin-2-amine	IC50	360 nM
3-[[(4S)-4-amino-5-(methanesulfonamido)-5-oxopentanoyl]amino]-5-chloro-2-hydroxybenzenesulfonic acid	EC50	390 nM	US-9253997: Alkylamine derivative
N-(2-phenoxyethyl)-2-[(2-phenylethyl)amino]-4-(3,4,5-trimethoxyphenyl)pyrimidine-5-carboxamide	IC50	400 nM
N-(1-Adamantyl)-5-(2-furanyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyra-zolo[1,5-a]pyrimidine-3-carboxamide	IC50	400 nM
2-[benzyl(methyl)amino]-N-(2-phenoxyethyl)-4-(3,4,5-trimethoxyphenyl)pyrimidine-5-carboxamide	IC50	470 nM
(2S)-2-amino-3-[(2-fluoro-5-sulfophenyl)carbamoylamino]propanoic acid	EC50	490 nM	US-9253997: Alkylamine derivative
N-(1-Adamantyl)-7,7-dimethyl-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimid-ine-3-carboxamide	IC50	580 nM
N-(1-Adamantyl)-5,7-diphenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	700 nM
2-(benzylamino)-N-(2-phenoxyethyl)-4-(3,4,5-trimethoxyphenyl)pyrimidine-5-carboxamide	IC50	730 nM
3-[[(4S)-4-amino-4-(5-benzyl-1,3,4-oxadiazol-2-yl)butanoyl]amino]-5-chloro-2-hydroxybenzenesulfonic acid	EC50	880 nM	US-9253997: Alkylamine derivative
(2S)-2-amino-3-[(2-methoxy-5-sulfophenyl)carbamoylamino]propanoic acid	EC50	1000 nM	US-9253997: Alkylamine derivative
3-[[(2S)-2-amino-2-carboxyethyl]carbamoylamino]-2-hydroxybenzoic acid	EC50	1000 nM	US-9253997: Alkylamine derivative
2-{[2-(3-methoxyphenyl)ethyl]amino}-N-(2-phenoxyethyl)-4-(3,4,5-trimethoxyphenyl)pyrimidine-5-carboxamide	IC50	1000 nM
6-[benzyl(ethyl)amino]-2-(2,6-dimethoxypyridin-3-yl)-N-(2-phenoxyethyl)pyridine-3-carboxamide	IC50	1050 nM
3-[[(2S)-2-amino-4-cyanobutoxy]carbonylamino]-5-chloro-2-hydroxybenzenesulfonic acid	EC50	1100 nM	US-9253997: Alkylamine derivative
(2S)-2-amino-3-[(2,4-dimethyl-5-sulfophenyl)carbamoylamino]propanoic acid	EC50	1100 nM	US-9253997: Alkylamine derivative
3-[[(4S)-4-amino-5-[2-(3-chlorophenyl)ethylamino]-5-oxopentanoyl]amino]-5-chloro-2-hydroxybenzenesulfonic acid	EC50	1200 nM	US-9253997: Alkylamine derivative
2-[methyl(2-phenylethyl)amino]-N-(2-phenoxyethyl)-4-(3,4,5-trimethoxyphenyl)pyrimidine-5-carboxamide	IC50	1500 nM

ChEMBL bioactivities

625 potent at pChembl≥5 of 638 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.74	IC50	0.018	nM	CHEMBL382741
10.66	IC50	0.022	nM	CHEMBL570593
10.47	IC50	0.034	nM	CHEMBL1204009
10.24	IC50	0.058	nM	CHEMBL180672
9.70	IC50	0.2	nM	CHEMBL570593
9.40	IC50	0.4	nM	CHEMBL597397
9.03	IC50	0.94	nM	CHEMBL1689060
8.85	IC50	1.4	nM	ATF-936
8.80	IC50	1.6	nM	CHEMBL591240
8.80	IC50	1.6	nM	CHEMBL1223714
8.77	IC50	1.7	nM	CHEMBL1689051
8.77	IC50	1.7	nM	CHEMBL1689057
8.74	IC50	1.8	nM	CHEMBL598436
8.70	EC50	2	nM	CHEMBL3093422
8.70	IC50	2	nM	CHEMBL1223772
8.70	IC50	2	nM	CHEMBL1689052
8.66	IC50	2.2	nM	CHEMBL1689055
8.64	IC50	2.3	nM	CHEMBL1688099
8.64	IC50	2.3	nM	CHEMBL1689049
8.62	IC50	2.4	nM	CHEMBL590539
8.62	IC50	2.4	nM	CHEMBL1689047
8.60	IC50	2.5	nM	CHEMBL597208
8.59	IC50	2.6	nM	CHEMBL1223771
8.57	IC50	2.7	nM	CHEMBL604506
8.52	EC50	3	nM	CHEMBL3093424
8.52	EC50	3	nM	CHEMBL3093421
8.52	EC50	3	nM	CHEMBL3980928
8.52	EC50	3	nM	CHEMBL3972910
8.52	EC50	3	nM	CHEMBL3937671
8.52	IC50	3	nM	CHEMBL2112075
8.52	IC50	3	nM	CHEMBL1689053
8.51	EC50	3.1	nM	CHEMBL5415372
8.47	IC50	3.4	nM	CHEMBL597194
8.47	IC50	3.4	nM	CHEMBL1689815
8.46	IC50	3.5	nM	CHEMBL1689809
8.43	EC50	3.7	nM	CHEMBL5428661
8.41	IC50	3.9	nM	CHEMBL598638
8.40	EC50	4	nM	CHEMBL3093425
8.40	EC50	4	nM	CHEMBL3895461
8.40	EC50	4	nM	CINACALCET
8.40	IC50	4	nM	CHEMBL1223712
8.40	IC50	4	nM	CHEMBL1223713
8.40	IC50	4	nM	CHEMBL1672970
8.39	IC50	4.1	nM	CHEMBL1689040
8.38	IC50	4.2	nM	CHEMBL597400
8.38	IC50	4.2	nM	CHEMBL597401
8.38	IC50	4.2	nM	CHEMBL1689050
8.37	EC50	4.3	nM	CHEMBL5430130
8.36	IC50	4.4	nM	CHEMBL591475
8.36	IC50	4.4	nM	CHEMBL1689811

PubChem BioAssay actives

628 with measured affinity, of 847 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[3-cyano-4-[(2R)-2-hydroxy-3-[(2-methyl-1-naphthalen-2-ylpropan-2-yl)amino]propoxy]phenyl]propanoic acid	440275: Displacement of 3H from human calcium receptor expressed in human HEK293 4.0-7 cells by liquid scintillation counting	ic50	<0.0001	uM
2-[(2R)-2-hydroxy-3-[(2-methyl-1-naphthalen-2-ylpropan-2-yl)amino]propoxy]benzonitrile	440274: Antagonist activity at human calcium receptor expressed in HEK293 4.0-7 cells assessed as inhibition of intracellular calcium release by FLIPR assay	ic50	<0.0001	uM
ethyl 3-[3-cyano-4-[(2R)-2-hydroxy-3-[(2-methyl-1-naphthalen-2-ylpropan-2-yl)amino]propoxy]phenyl]propanoate;hydrochloride	440274: Antagonist activity at human calcium receptor expressed in HEK293 4.0-7 cells assessed as inhibition of intracellular calcium release by FLIPR assay	ic50	<0.0001	uM
2-chloro-6-[(2R)-2-hydroxy-3-[(2-methyl-1-naphthalen-2-ylpropan-2-yl)amino]propoxy]benzonitrile	440275: Displacement of 3H from human calcium receptor expressed in human HEK293 4.0-7 cells by liquid scintillation counting	ic50	<0.0001	uM
1-[[3-(2-hydroxyethoxy)phenyl]methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazoline-2-thione	459697: Antagonist activity at human CaSR expressed in CCL39 cells assessed as inhibition of extracellular calcium-induced intracellular calcium transient by FLIPR assay	ic50	0.0004	uM
(5R)-N-[3-(4-ethylphenyl)pentan-3-yl]-2,7,7-trimethyl-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide;4-methylbenzenesulfonic acid	586952: Antagonist activity at CaSR expressed in CHO cells assessed as inhibition of [35S]GTPgammaS binding after 10 mins by scintillation counting	ic50	0.0009	uM
1-[(3-ethoxy-4-methoxyphenyl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one	459697: Antagonist activity at human CaSR expressed in CCL39 cells assessed as inhibition of extracellular calcium-induced intracellular calcium transient by FLIPR assay	ic50	0.0014	uM
7-methoxy-1-(2-methoxyethyl)-5-[(2-methylsulfanyl-3-pyridinyl)methyl]-2-(4-propan-2-ylphenyl)-4-(trifluoromethyl)benzimidazole	502175: Antagonist activity at human CaSR expressed in hamster fibroblasts assessed as inhibition of calcium mobilization	ic50	0.0016	uM
1-[(4-methylphenyl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one	459697: Antagonist activity at human CaSR expressed in CCL39 cells assessed as inhibition of extracellular calcium-induced intracellular calcium transient by FLIPR assay	ic50	0.0016	uM
(5R)-2,7,7-trimethyl-5-phenyl-N-[3-(4-propan-2-ylphenyl)pentan-3-yl]-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide;hydrochloride	586952: Antagonist activity at CaSR expressed in CHO cells assessed as inhibition of [35S]GTPgammaS binding after 10 mins by scintillation counting	ic50	0.0017	uM
(5R)-N-[3-(3-chloro-4-methoxyphenyl)pentan-3-yl]-2,7,7-trimethyl-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide;hydrochloride	586952: Antagonist activity at CaSR expressed in CHO cells assessed as inhibition of [35S]GTPgammaS binding after 10 mins by scintillation counting	ic50	0.0017	uM
1-[(3-methylphenyl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one	459697: Antagonist activity at human CaSR expressed in CCL39 cells assessed as inhibition of extracellular calcium-induced intracellular calcium transient by FLIPR assay	ic50	0.0018	uM
(5R)-N-[3-(4-methoxyphenyl)pentan-3-yl]-2,7,7-trimethyl-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide;hydrochloride	586952: Antagonist activity at CaSR expressed in CHO cells assessed as inhibition of [35S]GTPgammaS binding after 10 mins by scintillation counting	ic50	0.0020	uM
2-[[7-methoxy-1-(2-methoxyethyl)-2-(4-propan-2-ylphenyl)-4-(trifluoromethyl)benzimidazol-5-yl]methyl]-1,3-thiazole	502175: Antagonist activity at human CaSR expressed in hamster fibroblasts assessed as inhibition of calcium mobilization	ic50	0.0020	uM
3-[5-chloro-4-(4-sulfamoylphenyl)-1,3-thiazol-2-yl]-1-(3,3-diphenylpropyl)-1-(2-morpholin-4-ylethyl)urea	1058558: Activation of human CaSR	ec50	0.0020	uM
(5R)-2,7,7-trimethyl-5-phenyl-N-[3-(4-phenylmethoxyphenyl)pentan-3-yl]-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide;hydrochloride	586952: Antagonist activity at CaSR expressed in CHO cells assessed as inhibition of [35S]GTPgammaS binding after 10 mins by scintillation counting	ic50	0.0022	uM
(5R)-2,7,7-trimethyl-5-phenyl-N-(3-phenylpentan-3-yl)-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide;hydrochloride	586952: Antagonist activity at CaSR expressed in CHO cells assessed as inhibition of [35S]GTPgammaS binding after 10 mins by scintillation counting	ic50	0.0023	uM
(5R)-7,7-dimethyl-N-[3-(4-methylphenyl)pentan-3-yl]-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide;hydrochloride	586952: Antagonist activity at CaSR expressed in CHO cells assessed as inhibition of [35S]GTPgammaS binding after 10 mins by scintillation counting	ic50	0.0023	uM
2-(4-methylpiperazin-1-yl)-N-[3-[[2-oxo-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-1-yl]methyl]phenyl]acetamide	459697: Antagonist activity at human CaSR expressed in CCL39 cells assessed as inhibition of extracellular calcium-induced intracellular calcium transient by FLIPR assay	ic50	0.0024	uM
(5R)-2,7,7-trimethyl-N-[3-(4-methylphenyl)pentan-3-yl]-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide;hydrochloride	586952: Antagonist activity at CaSR expressed in CHO cells assessed as inhibition of [35S]GTPgammaS binding after 10 mins by scintillation counting	ic50	0.0024	uM
1-benzyl-5-(cyclopropylmethyl)-6-hydroxy-4-(4-propan-2-ylphenyl)quinazolin-2-one	459697: Antagonist activity at human CaSR expressed in CCL39 cells assessed as inhibition of extracellular calcium-induced intracellular calcium transient by FLIPR assay	ic50	0.0025	uM
7-methoxy-1-(2-methoxyethyl)-5-[(2-methylsulfinyl-3-pyridinyl)methyl]-2-(4-propan-2-ylphenyl)-4-(trifluoromethyl)benzimidazole	502175: Antagonist activity at human CaSR expressed in hamster fibroblasts assessed as inhibition of calcium mobilization	ic50	0.0026	uM
1-[(3-methoxyphenyl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one	459697: Antagonist activity at human CaSR expressed in CCL39 cells assessed as inhibition of extracellular calcium-induced intracellular calcium transient by FLIPR assay	ic50	0.0027	uM
(5R)-N-[3-(4-ethoxyphenyl)pentan-3-yl]-2,7,7-trimethyl-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide;hydrochloride	586952: Antagonist activity at CaSR expressed in CHO cells assessed as inhibition of [35S]GTPgammaS binding after 10 mins by scintillation counting	ic50	0.0030	uM
3-[5-chloro-4-[4-(methanesulfonamido)phenyl]-1,3-thiazol-2-yl]-1-(3,3-diphenylpropyl)-1-(2-morpholin-4-ylethyl)urea	1058558: Activation of human CaSR	ec50	0.0030	uM
1-(3,3-diphenylpropyl)-1-(2-morpholin-4-ylethyl)-3-[3-(4-sulfamoylphenyl)-1,2,4-thiadiazol-5-yl]urea	1058558: Activation of human CaSR	ec50	0.0030	uM
2-chloro-6-[(2R)-2-hydroxy-3-[(2-methyl-1-naphthalen-2-ylpropan-2-yl)amino]propoxy]benzonitrile;hydrochloride	372004: Binding affinity to human parathyroid calcium receptor 1 expressed in HEK293 4.0-7 cells by radioligand binding assay	ic50	0.0030	uM
2-fluoro-5-[(2R,4S)-2-[[[(1R)-1-naphthalen-1-ylethyl]amino]methyl]-3,4-dihydro-2H-chromen-4-yl]benzoic acid;hydrochloride	1998034: Agonist activity at human CaSR expresssed in HEK293 cells in presence of glucose by Fluo4NW dye based FLIPR assay	ec50	0.0031	uM
7,7-dimethyl-5-phenyl-N-(3-phenylpentan-3-yl)-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide	587911: Inhibition of CaSR expressed in CHO cells incubated with compound for 10 mins measured after 1 hr by [35S]GTPgammaS binding assay	ic50	0.0034	uM
2-[3-[[2-oxo-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-1-yl]methyl]phenoxy]acetic acid	459697: Antagonist activity at human CaSR expressed in CCL39 cells assessed as inhibition of extracellular calcium-induced intracellular calcium transient by FLIPR assay	ic50	0.0034	uM
7,7-dimethyl-5-phenyl-N-[2-[4-(trifluoromethyl)phenyl]propan-2-yl]-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide	587911: Inhibition of CaSR expressed in CHO cells incubated with compound for 10 mins measured after 1 hr by [35S]GTPgammaS binding assay	ic50	0.0035	uM
2-methyl-5-[(2S,4R)-2-[[[(1R)-1-naphthalen-1-ylethyl]amino]methyl]-3,4-dihydro-2H-chromen-4-yl]benzoic acid;hydrochloride	1998034: Agonist activity at human CaSR expresssed in HEK293 cells in presence of glucose by Fluo4NW dye based FLIPR assay	ec50	0.0037	uM
1-benzyl-6-hydroxy-4-(4-propan-2-ylphenyl)-5-prop-2-enylquinazolin-2-one	459697: Antagonist activity at human CaSR expressed in CCL39 cells assessed as inhibition of extracellular calcium-induced intracellular calcium transient by FLIPR assay	ic50	0.0039	uM
Cinacalcet	1998034: Agonist activity at human CaSR expresssed in HEK293 cells in presence of glucose by Fluo4NW dye based FLIPR assay	ec50	0.0040	uM
4-bromo-7-methoxy-1-(2-methoxyethyl)-5-[(2-methylsulfanyl-3-pyridinyl)methyl]-2-(4-propan-2-ylphenyl)benzimidazole	502175: Antagonist activity at human CaSR expressed in hamster fibroblasts assessed as inhibition of calcium mobilization	ic50	0.0040	uM
7-methoxy-1-(2-methoxyethyl)-5-[(2-methoxy-3-pyridinyl)methyl]-2-(4-propan-2-ylphenyl)-4-(trifluoromethyl)benzimidazole	502175: Antagonist activity at human CaSR expressed in hamster fibroblasts assessed as inhibition of calcium mobilization	ic50	0.0040	uM
4-[2-[(1R)-1-[(2R)-2-hydroxy-3-[(2-methyl-1-naphthalen-2-ylpropan-2-yl)amino]propoxy]ethyl]phenyl]benzoic acid	570222: Antagonist activity at human CaSR expressed in rat PC12h cells by reporter gene assay	ic50	0.0040	uM
1-[3,3-bis(2-fluorophenyl)propyl]-3-[5-chloro-4-(4-sulfamoylphenyl)-1,3-thiazol-2-yl]-1-(2-morpholin-4-ylethyl)urea	1058558: Activation of human CaSR	ec50	0.0040	uM
2,7,7-trimethyl-N-[3-(4-methylphenyl)pentan-3-yl]-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide;hydrochloride	586952: Antagonist activity at CaSR expressed in CHO cells assessed as inhibition of [35S]GTPgammaS binding after 10 mins by scintillation counting	ic50	0.0041	uM
(5R)-N-[3-(4-ethylphenyl)pentan-3-yl]-2,7,7-trimethyl-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide;hydrochloride	586952: Antagonist activity at CaSR expressed in CHO cells assessed as inhibition of [35S]GTPgammaS binding after 10 mins by scintillation counting	ic50	0.0042	uM
1-[(4-ethylphenyl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one	459697: Antagonist activity at human CaSR expressed in CCL39 cells assessed as inhibition of extracellular calcium-induced intracellular calcium transient by FLIPR assay	ic50	0.0042	uM
1-[(4-methoxyphenyl)methyl]-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one	459697: Antagonist activity at human CaSR expressed in CCL39 cells assessed as inhibition of extracellular calcium-induced intracellular calcium transient by FLIPR assay	ic50	0.0042	uM
2-methyl-3-[(2R,4S)-2-[[[(1R)-1-naphthalen-1-ylethyl]amino]methyl]-3,4-dihydro-2H-chromen-4-yl]benzoic acid;hydrochloride	1998034: Agonist activity at human CaSR expresssed in HEK293 cells in presence of glucose by Fluo4NW dye based FLIPR assay	ec50	0.0043	uM
1-benzyl-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one	459697: Antagonist activity at human CaSR expressed in CCL39 cells assessed as inhibition of extracellular calcium-induced intracellular calcium transient by FLIPR assay	ic50	0.0044	uM
7,7-dimethyl-5-phenyl-N-[4-[4-(trifluoromethyl)phenyl]heptan-4-yl]-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide	587911: Inhibition of CaSR expressed in CHO cells incubated with compound for 10 mins measured after 1 hr by [35S]GTPgammaS binding assay	ic50	0.0044	uM
(5R)-N-[3-(3-fluoro-4-methoxyphenyl)pentan-3-yl]-2,7,7-trimethyl-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide;hydrochloride	586952: Antagonist activity at CaSR expressed in CHO cells assessed as inhibition of [35S]GTPgammaS binding after 10 mins by scintillation counting	ic50	0.0046	uM
7,7-dimethyl-N-[3-(4-methylphenyl)pentan-3-yl]-2-methylsulfanyl-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide;hydrochloride	586952: Antagonist activity at CaSR expressed in CHO cells assessed as inhibition of [35S]GTPgammaS binding after 10 mins by scintillation counting	ic50	0.0047	uM
(5R)-N-[3-(4-acetylphenyl)pentan-3-yl]-2,7,7-trimethyl-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide	586952: Antagonist activity at CaSR expressed in CHO cells assessed as inhibition of [35S]GTPgammaS binding after 10 mins by scintillation counting	ic50	0.0048	uM
3-[4-[(2R)-2-hydroxy-3-[(2-methyl-1-naphthalen-2-ylpropan-2-yl)amino]propoxy]phenyl]propanoic acid	440275: Displacement of 3H from human calcium receptor expressed in human HEK293 4.0-7 cells by liquid scintillation counting	ic50	0.0048	uM
7,7-dimethyl-N-[3-(4-methylphenyl)pentan-3-yl]-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide;hydrochloride	587911: Inhibition of CaSR expressed in CHO cells incubated with compound for 10 mins measured after 1 hr by [35S]GTPgammaS binding assay	ic50	0.0049	uM

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Calcium	decreases reaction, increases uptake, increases activity, increases reaction, increases expression (+7 more)	9
2-aminoethoxydiphenyl borate	decreases reaction, increases activity, increases uptake, affects binding	2
Calcium Chloride	increases phosphorylation, increases reaction, increases activity	2
Lanthanum	increases uptake, affects binding, decreases reaction, increases activity	2
bisphenol A	affects cotreatment, increases methylation	1
chelerythrine	decreases reaction, increases uptake	1
phorbolol myristate acetate	increases phosphorylation, increases reaction	1
calyculin A	increases phosphorylation, increases reaction	1
1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione	decreases reaction, increases uptake	1
1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole	decreases reaction, increases uptake	1
bisindolylmaleimide I	increases reaction, decreases reaction, increases phosphorylation	1
CGP 52608	affects binding, increases reaction	1
N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine	affects reaction, increases response to substance, increases reaction	1
methyl-beta-cyclodextrin	decreases reaction, increases uptake	1
NPS R-467	decreases reaction, increases phosphorylation, increases reaction	1
abrine	increases expression	1
2-quinoxaline-carboxamide-N-adamantan-1-yl	decreases activity, decreases reaction, increases abundance, increases expression, decreases response to substance (+1 more)	1
Resveratrol	affects cotreatment, decreases expression	1
Zoledronic Acid	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Aluminum Chloride	increases activity	1
Amikacin	increases activity	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Flufenamic Acid	increases uptake, increases reaction	1
Gentamicins	increases activity, increases phosphorylation, increases reaction, affects binding	1
Methotrexate	decreases expression	1
Neomycin	affects binding, increases activity, increases phosphorylation, increases reaction	1
Nickel	decreases activity, decreases reaction, increases abundance, increases expression, decreases response to substance (+3 more)	1
Phosphorus	affects abundance	1
Plant Extracts	affects cotreatment, decreases expression	1

ChEMBL screening assays

45 unique, capped per target: 32 functional, 13 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1039645	Functional	Activity at human CaSR expressed in HEK293 cells assessed as calcium release by FLIPR assay	Discovery and optimization of substituted 1-(1-phenyl-1H-pyrazol-3-yl)methanamines as potent and efficacious type II calcimimetics. — J Med Chem
CHEMBL1055305	Binding	Displacement of 3H from human calcium receptor expressed in human HEK293 4.0-7 cells by liquid scintillation counting	Antagonists of the calcium receptor. 2. Amino alcohol-based parathyroid hormone secretagogues. — J Med Chem

Cellosaurus cell lines

7 cell lines: 3 induced pluripotent stem cell, 2 spontaneously immortalized cell line, 1 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A8WH	HPCASRi002-A	Induced pluripotent stem cell	Male
CVCL_C1PC	CSSi015-A	Induced pluripotent stem cell	Male
CVCL_E339	HEK-CaSR	Transformed cell line	Female
CVCL_E4C7	HPCASRi002-Ae4	Induced pluripotent stem cell	Male
CVCL_H408	CHO-K1/CASR	Spontaneously immortalized cell line	Female
CVCL_KU66	U2OS CASR Gq	Cancer cell line	Female
CVCL_ZK52	GeneBLAzer CaSR-Gqo5-NFAT-bla CHO-K1	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

317 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00002146	PHASE4	COMPLETED	Safety and Efficacy of Intravenous Magnesium Sulfate in Modulating Changes in Symptoms and Divalent Cation Levels Associated With Foscavir Therapy: A Phase IV Randomized, Double-Blind, Placebo-Controlled, Cross-Over, Pilot Study
NCT00668200	PHASE4	COMPLETED	Impact on Reducing the Incidence of Low Serum Calcium by Providing Educational Materials on the Need to Take Daily Supplemental Calcium and Vitamin D to Patients With Paget’s Disease Treated With Reclast®
NCT01632514	PHASE4	UNKNOWN	Vitamin D Deficiency and Postoperative Hypocalcemia
NCT04012476	PHASE4	UNKNOWN	Determination of Parathyroid Function by Fluorescence With Indocyanine Green (ICG) After Total Thyroidectomy
NCT04412694	PHASE4	UNKNOWN	The Effect of Preoperative Oral Dexamethasone Supplementation on the Outcome of Thyroidectomised Patients.
NCT04491357	PHASE4	UNKNOWN	Prophylactic Infusion of Calcium Gluconate Reducing the Rate of Hypocalcaemia After Total Thyroidectomy
NCT05216419	PHASE4	COMPLETED	Prevention of Postoperative Hypocalcemia of Oral Vitamin D Supplementation Before Total Thyroidectomy
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
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
NCT03935984	PHASE4	RECRUITING	Calcitonin Pre-treatment to Improve SPECT-CT Sensitivity
NCT04750460	PHASE3	COMPLETED	Injection of Teriparatide to Prevent Hypocalcemia After Parathyroidectomy in Dialysis Patients (TeriCa).
NCT04775381	PHASE3	RECRUITING	Total Post-thyroidectomy Hypocalcemia After Preoperative Cholecalciferol Supplementation
NCT05680818	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy and Safety of Encaleret Compared to Standard of Care in Participants With ADH1
NCT05953376	PHASE3	WITHDRAWN	Empiric Calcium in Massive Transfusion
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00325104	PHASE3	COMPLETED	Cinacalcet to Treat Familial 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
NCT01460030	PHASE3	COMPLETED	An Intra-individual Titration Study of KRN1493 for the Treatment of Hypercalcemia in Patients With Parathyroid Carcinoma or Intractable Primary Hyperparathyroidism
NCT00743782	PHASE2	COMPLETED	Comparing Pump With Subcutaneous Injection Delivery of PTH 1-34 in the Management of Chronic Hypoparathyroidism
NCT04581629	PHASE2	COMPLETED	Safety, Tolerability, and Efficacy of Encaleret in Participants With Autosomal Dominant Hypocalcemia (ADH) Type 1
NCT00001151	PHASE2	TERMINATED	Studies With 1,25-Dihydroxycholecalciferol
NCT00053378	PHASE2	COMPLETED	A Study to Examine the Use of Zemplar to Increase Serum Calcium Levels in ICU Subjects
NCT00623974	PHASE2	TERMINATED	Teriparatide (Forteo) in the Treatment of Patients With Postoperative Hypocalcemia
NCT00630214	PHASE2	COMPLETED	Prevention of Hypocalcemia in Patients Undergoing Total Thyroidectomy Plus Central Neck Dissection
NCT01868750	PHASE2	COMPLETED	Phase II Pre-operative Vitamin D Supplementation to Prevent Post-thyroidectomy Hypocalcemia
NCT02204579	PHASE2	COMPLETED	A Study to Determine the Effects of NPSP795 on the Calcium-sensing Receptor in Subjects With Autosomal Dominant Hypocalcemia as Measured by PTH Levels and Blood Calcium Concentrations
NCT05732883	PHASE2	RECRUITING	The Use of Dexamethasone in Total Thyroidectomy to Improve Voice Outcome and Hypocalcaemia
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00001277	PHASE2	COMPLETED	Studies of Elevated Parathyroid Activity
NCT00744302	PHASE2	COMPLETED	Study of 1.25 mmol/L Calcium Dialysate on Mineral Metabolism in Haemodialysis Patients.
NCT02274623	PHASE1	COMPLETED	Effect of CTAP101 Capsules on Ca/iPTH in Advanced Breast/Prostate Cancer Patients Treated With Denosumab/Zoledronic Acid
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism