PTH

Summary

PTH (parathyroid hormone, HGNC:9606) is a protein-coding gene on chromosome 11p15.3, encoding Parathyroid hormone (P01270). Parathyroid hormone elevates calcium level by dissolving the salts in bone and preventing their renal excretion.

This gene encodes a member of the parathyroid family of proteins. The encoded preproprotein is proteolytically processed to generate a protein that binds to the parathyroid hormone/parathyroid hormone-related peptide receptor and regulates blood calcium and phosphate levels. Excess production of the encoded protein, known as hyperparathyroidism, can result in hypercalcemia and kidney stones. On the other hand, defective processing of the encoded protein may lead to hypoparathyroidism, which can result in hypocalcemia and numbness. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5741 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypoparathyroidism, familial isolated 1 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 52 total — 5 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 15
• MANE Select transcript: NM_000315

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9606
Approved symbol	PTH
Name	parathyroid hormone
Location	11p15.3
Locus type	gene with protein product
Status	Approved
Aliases	PTH1
Ensembl gene	ENSG00000152266
Ensembl biotype	protein_coding
OMIM	168450
Entrez	5741

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000282091, ENST00000529816

RefSeq mRNA: 2 — MANE Select: NM_000315 NM_000315, NM_001316352

CCDS: CCDS7812

Canonical transcript exons

ENST00000282091 — 3 exons

Exon	Start	End
ENSE00001004377	13492770	13492860
ENSE00001004379	13492054	13492666
ENSE00001306506	13495911	13495997

Expression profiles

Bgee: expression breadth broad, 94 present calls, max score 84.78.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5301 / max 459.6596, expressed in 10 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118726	0.3733	8
118727	0.1569	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.78	gold quality
pigmented layer of retina	UBERON:0001782	63.05	gold quality
endometrium epithelium	UBERON:0004811	56.70	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
quadriceps femoris	UBERON:0001377	49.88	gold quality
metanephric glomerulus	UBERON:0004736	49.61	gold quality
thymus	UBERON:0002370	49.55	gold quality
vastus lateralis	UBERON:0001379	49.48	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
oviduct epithelium	UBERON:0004804	48.46	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
kidney epithelium	UBERON:0004819	48.11	gold quality
epithelial cell of pancreas	CL:0000083	48.07	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
cervix epithelium	UBERON:0004801	48.04	gold quality
tongue squamous epithelium	UBERON:0006919	47.92	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality
layer of synovial tissue	UBERON:0007616	47.54	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-79	yes	44048.12
E-ANND-3	no	1.13

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
MMP13	Activation

Upstream regulators (CollecTRI, top): AP1, APEX1, ATF4, CREM, ESR1, ETS1, FOXA2, FOXC1, GATA1, GATA3, GCM2, HNF1B, IRF6, JUN, JUNB, KHSRP, LRRFIP1, MAFB, MAZ, MEF2A, NFIL3, NR1H2, NR3C1, NR4A2, PAX3, POU1F1, RUNX2, RXRB, SP1, SP3, SP7, TCF3, VDR, XBP1, ZNF384

miRNA regulators (miRDB)

62 targeting PTH, 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-3134	100.00	66.43	777
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
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-106A-5P	99.90	73.94	2683
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-646	99.68	67.84	1645

Literature-anchored findings (GeneRIF, showing 40)

• The presence of an evolutionarily conserved arginine residue on the hydrophobic face of parathyroid hormone’s amphiphilic alpha-helix strongly affects PTH receptor binding and adenylyl cyclase-stimulating activities. (PMID:11467957)
• We report that PTH induced the appearance of voltage sensitive calcium channels. Furthermore, PTH increased ceramide but not diacylglycerol content. (PMID:11814621)
• data do not support the PTH gene as a quantitative trait locus(QTL)underlying hip or spine bone mineral density variation (PMID:11918225)
• New signaling pathway for parathyroid hormone and cyclic AMP action on extracellular-regulated kinase and cell proliferation in bone cells (PMID:11956184)
• REVIEW: role in coronary heart disease in uremic patients (PMID:12207101)
• demonstration that PTH directly stimulates RANKL expression via a PKA-CREB pathway (PMID:12364326)
• Review. The effects of intermittent and continuous PTH exposure on periosteal bone expansion & osteoblast apoptosis are reviewed. (PMID:12369776)
• Residues 15-20, particularly residue 19, of PTH contribute to the receptor interaction process via a mechanism that involves the N-terminal portion of the ligand and the juxtamembrane region of the receptor. (PMID:12403624)
• Lack of evidence for the parathyroid hormone gene as a quantitative trait locus underlying the bone phenotypic variation in the Chinese. (PMID:12893275)
• 1-21 region of PTH binds to the extracellular face of the type 1 PTH receptorPTHRP domain as an alpha-helix. (PMID:12947048)
• estrogen receptor alpha Px haplotype and collagen IA1 s allele may be involved in causing the phenotypic expression of higher circulating levels of parathyroid hormone and higher bone turnover, which may lead to bone loss (PMID:14506618)
• High-resolution structures clearly illustrate the structural differences between linear and cyclic PTH(1-14) fragments, supporting the hypothesis that an alpha-helix is the preferred bioactive conformation of the N-terminal fragment of PTH. (PMID:14730973)
• role in programing skeletal development in utero (PMID:14969386)
• Studies suggest that an alpha-helix is the preferred conformation for the residue 15-20 region of PTH and that residues 10-14 are also required for full affinity and potency of the hormone. (PMID:15035617)
• Serum PTH is a predictor of time to first fall in the frail elderly independent of vitamin D status and measures of general health. (PMID:15070914)
• The rise in serum PTH appeared to start when serum 25(OH)D fell less than 80 nmol/liter. (PMID:15070925)
• results revealed a novel potent effect of PTH and vitamin D(3) plus BMPs in inducing bone development by human mesenchymal stem cells (PMID:15186723)
• 11-residue short oligopeptide analogues of PTH tend to form an alpha-helical structure and the different activities of those analogues could be associated with residue specificity rather than the secondary conformational structure. (PMID:15227728)
• These data support the hypothesis that hPTH (1-34) initially stimulates osteoblast maturation and function, which in turn leads to osteoclast activation and a gradual rebalancing of bone formation and resorption. (PMID:15240611)
• there is a proximal NF-Y-binding site in the hPTH promoter, which has a role in enhancing transcription (PMID:15297458)
• in patients with sporadic idiopathic hypoparathyroidism, neither the clinical manifestations nor the biochemical indexes are related to the occurrence of mutations or single nucleotide polymorphisms in the PTH gene (PMID:15472173)
• PTH attenuates the stress-induced JNK signaling pathway in osteoblasts via induction of MKP-1 synthesis but inhibits the p42/44 MAPK pathway mainly via transcription-independent mechanisms. (PMID:15504937)
• calcineurin regulates AUF1 posttranslationally in vitro and PTH gene expression in vivo but still allows its physiological regulation by calcium and phosphate (PMID:15514034)
• Inverse correlation between intact serum parathyroid homone with percent of left ventricular ejection fraction in non-diabetic hemodialysis patients was observed. (PMID:15515479)
• These results indicate that 1,25(OH)2D3 may affect transcription of the human PTH gene both by competitive binding of VDR and NF-Y, and by modulating transcriptional activity of NF-Y. (PMID:15707954)
• PTH is a potent down-regulator of vitamin D receptor expression. (PMID:15769857)
• Carboxy-terminal fragment of PTH was equivalent to the intact PTH molecule in stimulating [3H]thymidine incorporation in HUVEC. (PMID:15808916)
• alternative cis-acting protein-binding elements may determine the regulation of PTH mRNA stability in response to changes in serum calcium and phosphate (PMID:15824859)
• data thus provide direct evidence for important roles of the C-terminal domain of PTH in determining high affinity binding and activation of the P1R receptor (PMID:15826940)
• Transactivation of the PTH promoters is observed by Sp proteins and the NF-Y complex. (PMID:15890770)
• a possible role for the Wnt signaling pathway in PTH actions in bone (PMID:15962290)
• Suppression of Sost by PTH represents a novel mechanism for hormonal control of osteoblastogenesis mediated by osteocytes. (PMID:16081646)
• non-(1-84) PTH fragments are composed of a family of fragments which may be generated by specific or progressive cleavage at the N region (PMID:16105030)
• Mid-region of PTH-(1-34) has a role in fixing, by extensive contacts with receptor, entry of N-terminal helix of the hormone into a heptahelical bundle between TM-1 & TM-2. This anchorage would orient the amino terminus into position to activate receptor. (PMID:16475791)
• blood pressure and serum parathyroid hormone (PTH) are associated. (PMID:16682833)
• based on the absence of identifiable DNA sequence alterations in parathyroid disorders, it is unlikely that mutation of the PTH 3’-UTR contributes frequently to their pathogenesis (PMID:17121534)
• An increased risk of metabolic syndrome with elevated PTH levels in older men. (PMID:17351276)
• Raloxifene treatment reduces bone turnover biochemical markers, parathyroid hormone and induces 25-OH vitamin D in postmenopausal women. (PMID:17823083)
• Present an atypical case of leukemic transformation in myelofibrosis associated with diffuse osteolytic lesions and extremely elevated TNF-alpha and lactate dehydrogenase (LDH). Parathormone was not disturbed. (PMID:17976926)
• crosstalk between PTH/cAMP signaling and canonical Wnt signaling using the human osteoblastic cell line Saos-2 (PMID:17990294)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pth1b	ENSDARG00000091961
danio_rerio	pth1a	ENSDARG00000093738
mus_musculus	Pth	ENSMUSG00000059077
rattus_norvegicus	Pth	ENSRNOG00000014318

Protein

Protein identifiers

Parathyroid hormone — P01270 (reviewed: P01270)

Alternative names: Parathormone, Parathyrin

All UniProt accessions (1): P01270

UniProt curated annotations — full annotation on UniProt →

Function. Parathyroid hormone elevates calcium level by dissolving the salts in bone and preventing their renal excretion. Acts by binding to its receptor, PTH1R, activating G protein-coupled receptor signaling. Stimulates [1-14C]-2-deoxy-D-glucose (2DG) transport and glycogen synthesis in osteoblastic cells.

Subunit / interactions. Interacts with PTH1R (via N-terminal extracellular domain).

Subcellular location. Secreted.

Disease relevance. Hypoparathyroidism, familial isolated, 1 (FIH1) [MIM:146200] A form of hypoparathyroidism, a disorder characterized by hypocalcemia and hyperphosphatemia due to a deficiency of parathyroid hormone. Clinical features include seizures, tetany and cramps. FIH1 inheritance can be autosomal dominant or recessive. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the parathyroid hormone family.

RefSeq proteins (2): NP_000306, NP_001303281 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001415	PTH/PTH-rel	Family
IPR003625	PTH	Family

Pfam: PF01279

UniProt features (17 total): mutagenesis site 6, helix 2, region of interest 2, sequence variant 2, signal peptide 1, propeptide 1, sequence conflict 1, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

26 structures.

PDB	Method	Resolution (Å)
1ET1	X-RAY DIFFRACTION	0.9
3C4M	X-RAY DIFFRACTION	1.95
8T5F	X-RAY DIFFRACTION	1.99
8FLQ	ELECTRON MICROSCOPY	2.55
8HA0	ELECTRON MICROSCOPY	2.62
7VVL	ELECTRON MICROSCOPY	2.8
7Y36	ELECTRON MICROSCOPY	2.8
9JR2	ELECTRON MICROSCOPY	2.8
9JR3	ELECTRON MICROSCOPY	2.8
7VVM	ELECTRON MICROSCOPY	3.2
7VVK	ELECTRON MICROSCOPY	3.3
8HAO	ELECTRON MICROSCOPY	3.76
7VVN	ELECTRON MICROSCOPY	3.8
7VVO	ELECTRON MICROSCOPY	4.1
1BWX	SOLUTION NMR
1FVY	SOLUTION NMR
1HPH	SOLUTION NMR
1HPY	SOLUTION NMR
1HTH	SOLUTION NMR
1ZWA	SOLUTION NMR
1ZWB	SOLUTION NMR
1ZWD	SOLUTION NMR
1ZWE	SOLUTION NMR
1ZWF	SOLUTION NMR
1ZWG	SOLUTION NMR
2L1X	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01270-F1	72.93	0.31

Antibody-complex structures (SAbDab): 11 — 7VVK, 7VVL, 7VVM, 7VVN, 7VVO, 7Y36, 8FLQ, 8HA0, 8HAO, 9JR2, 9JR3

Functional residue map

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

Mutagenesis-validated functional residues (6):

Position	Phenotype
54	strongly reduced affinity for pth1r.
55	strongly reduced affinity for pth1r.
58	reduced affinity for pth1r.
59	strongly reduced affinity for pth1r.
16	abolishes processing of the precursor; when associated with variant r-18.
51	reduced affinity for pth1r.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-373080	Class B/2 (Secretin family receptors)
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 275 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_RESPONSE_TO_ETHANOL, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, GOBP_INOSITOL_PHOSPHATE_METABOLIC_PROCESS, GOBP_POLYOL_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CYCLIC_NUCLEOTIDE_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_ALCOHOL_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, BONCI_TARGETS_OF_MIR15A_AND_MIR16_1

GO Biological Process (41): skeletal system development (GO:0001501), transcription by RNA polymerase II (GO:0006366), intracellular calcium ion homeostasis (GO:0006874), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), Rho protein signal transduction (GO:0007266), cell-cell signaling (GO:0007267), hormone-mediated apoptotic signaling pathway (GO:0008628), macromolecule biosynthetic process (GO:0009059), response to xenobiotic stimulus (GO:0009410), positive regulation of signal transduction (GO:0009967), response to lead ion (GO:0010288), regulation of gene expression (GO:0010468), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), magnesium ion homeostasis (GO:0010960), bone mineralization (GO:0030282), positive regulation of bone mineralization (GO:0030501), negative regulation of chondrocyte differentiation (GO:0032331), response to vitamin D (GO:0033280), bone resorption (GO:0045453), response to ethanol (GO:0045471), positive regulation of glycogen biosynthetic process (GO:0045725), positive regulation of transcription by RNA polymerase II (GO:0045944), cAMP metabolic process (GO:0046058), positive regulation of D-glucose import across plasma membrane (GO:0046326), response to cadmium ion (GO:0046686), homeostasis of number of cells within a tissue (GO:0048873), phosphate ion homeostasis (GO:0055062), positive regulation of inositol phosphate biosynthetic process (GO:0060732), response to parathyroid hormone (GO:0071107), response to fibroblast growth factor (GO:0071774), positive regulation of cell proliferation in bone marrow (GO:0071864), negative regulation of apoptotic process in bone marrow cell (GO:0071866), positive regulation of osteoclast proliferation (GO:0090290), adenylate cyclase-activating G protein-coupled cAMP receptor signaling pathway (GO:0140582), negative regulation of bone mineralization involved in bone maturation (GO:1900158), signal transduction (GO:0007165), response to nutrient levels (GO:0031667), positive regulation of ossification (GO:0045778)

GO Molecular Function (6): hormone activity (GO:0005179), parathyroid hormone receptor binding (GO:0031856), type 1 parathyroid hormone receptor binding (GO:0031857), receptor ligand activity (GO:0048018), peptide hormone receptor binding (GO:0051428), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
GPCR ligand binding	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	3
gene expression	3
regulation of gene expression	2
system development	1
DNA-templated transcription	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
G protein-coupled receptor activity	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
small GTPase-mediated signal transduction	1
cell communication	1
signaling	1
hormone-mediated signaling pathway	1
apoptotic signaling pathway	1
biosynthetic process	1
macromolecule metabolic process	1
response to chemical	1
regulation of signal transduction	1
positive regulation of cell communication	1
positive regulation of signaling	1
positive regulation of response to stimulus	1
response to metal ion	1
regulation of macromolecule biosynthetic process	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
ossification	1
biomineral tissue development	1
bone mineralization	1
regulation of bone mineralization	1
positive regulation of ossification	1
positive regulation of biomineral tissue development	1
chondrocyte differentiation	1
regulation of chondrocyte differentiation	1
negative regulation of cell differentiation	1
negative regulation of cartilage development	1
response to vitamin	1
response to lipid	1

Protein interactions and networks

STRING

1942 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PTH	PTH1R	Q03431	999
PTH	PTHLH	P12272	999
PTH	FGF23	Q9GZV9	976
PTH	PTH2R	P49190	963
PTH	CASR	P41180	950
PTH	BGLAP	P02818	942
PTH	CYP27B1	O15528	940
PTH	IGF1	P01343	911
PTH	INS	P01308	909
PTH	GCG	P01275	889
PTH	SOST	Q9BQB4	887
PTH	GCM2	O75603	884
PTH	LRP2	P98164	884
PTH	ALB	P02768	881
PTH	TNFSF11	O14788	875

IntAct

13 interactions, top by confidence:

A	B	Type	Score
PTH1R	PTH	psi-mi:“MI:0915”(physical association)	0.610
PTH1R	PTH	psi-mi:“MI:0407”(direct interaction)	0.610
ASPH	PTH	psi-mi:“MI:0915”(physical association)	0.560
PTH	ASPH	psi-mi:“MI:0915”(physical association)	0.560
P		psi-mi:“MI:0914”(association)	0.350
PTH	BAG6	psi-mi:“MI:0915”(physical association)	0.000
PTH	FEZ1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (12): PTH (Synthetic Lethality), BAG6 (Two-hybrid), FEZ1 (Two-hybrid), ASPH (Two-hybrid), PTH (Biochemical Activity), PTH (Reconstituted Complex), PTH (Affinity Capture-MS), PTH (Reconstituted Complex), PTH (Reconstituted Complex), PTH (Co-crystal Structure), PTH (Cross-Linking-MS (XL-MS)), PTH (Affinity Capture-Western)

ESM2 similar proteins: A8MXK1, O09163, O46633, O54713, O76096, O95684, P01148, P01268, P01269, P01270, P01344, P04089, P07352, P07456, P07490, P10286, P10764, P13562, P14745, P15696, P17647, P23695, P33717, P37042, P41694, P49921, P51459, P51462, P52212, P55247, Q05078, Q08279, Q27IM2, Q28588, Q29423, Q2YDD1, Q3SXP7, Q4R7M4, Q4R7V3, Q5GAN6

Diamond homologs: P01268, P01269, P01270, P04089, P15743, P52212, Q27IM2, Q9GL67, Q9XT35, Q9Z0L6

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PTH	up-regulates	PTH2R	binding
PTH	up-regulates	PTH1R	binding
GCM2	“up-regulates quantity by expression”	PTH	“transcriptional regulation”
PTH	“up-regulates quantity by expression”	MMP13	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	4
Uncertain significance	27
Likely benign	5
Benign	10

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
13756	NM_000315.4(PTH):c.52T>C (p.Cys18Arg)	Pathogenic
13757	NM_000315.4(PTH):c.86+1G>C	Pathogenic
13758	NM_000315.4(PTH):c.67T>C (p.Ser23Pro)	Pathogenic
1917357	NM_000315.4(PTH):c.86+4A>T	Pathogenic
2422867	NC_000011.9:g.(?13513952)(13514402_?)del	Pathogenic
1338322	NM_000315.4(PTH):c.46_47delinsAA (p.Ala16Lys)	Likely pathogenic
13759	NM_000315.4(PTH):c.247C>T (p.Arg83Ter)	Likely pathogenic
379458	NM_000315.4(PTH):c.166C>T (p.Arg56Cys)	Likely pathogenic
4537488	NM_000315.4(PTH):c.1_2insGCAT (p.Met1fs)	Likely pathogenic

SpliceAI

249 predictions. Top by Δscore:

Variant	Effect	Δscore
11:13492765:CTT:C	donor_loss	1.0000
11:13492766:TTA:T	donor_loss	1.0000
11:13492767:TA:T	donor_loss	1.0000
11:13492768:A:AC	donor_gain	1.0000
11:13492769:C:CT	donor_gain	1.0000
11:13492769:CTT:C	donor_gain	1.0000
11:13492769:CTTA:C	donor_gain	1.0000
11:13492769:CTTAA:C	donor_gain	1.0000
11:13492773:A:C	donor_gain	1.0000
11:13492856:CTTCA:C	acceptor_gain	1.0000
11:13492857:TTCA:T	acceptor_gain	1.0000
11:13492859:CA:C	acceptor_gain	1.0000
11:13492861:C:CC	acceptor_gain	1.0000
11:13492662:TCTTC:T	acceptor_loss	0.9900
11:13492663:CTTC:C	acceptor_gain	0.9900
11:13492665:TCCTG:T	acceptor_loss	0.9900
11:13492667:C:A	acceptor_loss	0.9900
11:13492667:C:CC	acceptor_gain	0.9900
11:13492764:ACTT:A	donor_loss	0.9900
11:13492765:CTTA:C	donor_gain	0.9900
11:13492769:CT:C	donor_gain	0.9900
11:13492772:A:AC	donor_gain	0.9900
11:13492858:TCA:T	acceptor_gain	0.9900
11:13492859:CAC:C	acceptor_gain	0.9900
11:13492859:CACTA:C	acceptor_loss	0.9900
11:13492861:CTAAA:C	acceptor_loss	0.9900
11:13492862:T:A	acceptor_loss	0.9900
11:13492870:C:CT	acceptor_gain	0.9900
11:13495907:TTA:T	donor_loss	0.9900
11:13495908:TA:T	donor_loss	0.9900

AlphaMissense

761 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:13492589:A:G	L55P	0.989
11:13492591:C:A	W54C	0.980
11:13492591:C:G	W54C	0.980
11:13492577:A:G	L59P	0.979
11:13492636:C:A	M39I	0.973
11:13492636:C:G	M39I	0.973
11:13492636:C:T	M39I	0.973
11:13492593:A:G	W54R	0.972
11:13492593:A:T	W54R	0.972
11:13492649:T:A	E35V	0.970
11:13492628:A:G	L42P	0.967
11:13492600:T:A	R51S	0.966
11:13492600:T:G	R51S	0.966
11:13492640:A:G	L38P	0.964
11:13492651:A:C	S34R	0.963
11:13492651:A:T	S34R	0.963
11:13492653:T:G	S34R	0.963
11:13492616:A:G	L46P	0.957
11:13492634:T:G	H40P	0.952
11:13492619:T:G	H45P	0.942
11:13492637:A:G	M39T	0.941
11:13492660:T:A	R31S	0.936
11:13492660:T:G	R31S	0.936
11:13492586:C:G	R56P	0.935
11:13492649:T:C	E35G	0.935
11:13492649:T:G	E35A	0.925
11:13492601:C:A	R51I	0.915
11:13492611:A:G	S48P	0.912
11:13492655:A:T	V33E	0.912
11:13492589:A:T	L55Q	0.910

dbSNP variants (sampled 300 via entrez): RS1000612797 (11:13493744 C>T), RS1000666957 (11:13493404 A>G), RS1001995677 (11:13494230 G>C), RS1002240330 (11:13494033 A>G,T), RS1002765323 (11:13497717 G>A), RS1003366300 (11:13496086 C>T), RS1003396465 (11:13495969 A>T), RS1005237079 (11:13496286 A>G), RS1005822377 (11:13497910 T>G), RS1006011428 (11:13492847 A>G), RS1006133451 (11:13497571 A>G), RS1006397774 (11:13494807 A>G), RS1006953199 (11:13498178 C>T), RS1007537840 (11:13492007 A>T), RS1008596291 (11:13493361 T>A)

Disease associations

OMIM: gene MIM:168450 | disease phenotypes: MIM:146200

GenCC curated gene-disease

Disease	Classification	Inheritance
hypoparathyroidism, familial isolated 1	Strong	Autosomal dominant
familial isolated hypoparathyroidism due to impaired PTH secretion	Supportive	Autosomal dominant

Mondo (4): hypoparathyroidism, familial isolated 1 (MONDO:0007796), primary hyperparathyroidism (MONDO:0010837), familial hypoparathyroidism (MONDO:0016390), familial isolated hypoparathyroidism due to impaired PTH secretion (MONDO:0016000)

Orphanet (1): Familial isolated hypoparathyroidism (Orphanet:2238)

HPO phenotypes

15 total (16 of 15 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000121	Nephrocalcinosis
HP:0000518	Cataract
HP:0000737	Irritability
HP:0000829	Hypoparathyroidism
HP:0001281	Tetany
HP:0002199	Hypocalcemic seizures
HP:0002514	Cerebral calcification
HP:0002901	Hypocalcemia
HP:0002905	Hyperphosphatemia
HP:0003593	Infantile onset
HP:0025303	Episodic
HP:0031817	Decreased circulating parathyroid hormone level
HP:0031990	Chvostek sign
HP:0008200	Primary hyperparathyroidism

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000515_1	Bone mineral density	4.000000e-07
GCST002541_84	Menarche (age at onset)	7.000000e-20
GCST003991_21	Childhood ear infection	6.000000e-07
GCST004897_2	Progression free survival in serous epithelial ovarian cancer treated with carboplatin and paclitaxel	1.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0007904	susceptibility to childhood ear infection measurement
EFO:0004920	progression free survival

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D049950	Hyperparathyroidism, Primary	C19.642.355.239
C537156	Hypoparathyroidism familial isolated (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6254	PTH		0.00	0

Binding affinities (BindingDB)

16 measured of 17 human assays (17 total across all organisms); most potent 16 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[3,5-dimethyl-4-[2-[[4-oxo-2-[4-(trifluoromethoxy)phenyl]-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]phenyl]-1,3-diazaspiro[4.4]nonane-2,4-dione	EC50	3600 nM	US-9428505: Hydantoin derivative
1-[3,5-dimethyl-4-[2-[[4-oxo-2-[4-(trifluoromethoxy)phenyl]-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]phenyl]-5,5-dimethylimidazolidine-2,4-dione	EC50	4100 nM	US-9428505: Hydantoin derivative
3-[3-methyl-4-[2-[[4-oxo-2-[3-(trifluoromethoxy)phenyl]-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]phenyl]imidazolidine-2,4-dione	EC50	4800 nM	US-9428505: Hydantoin derivative
1-[4-[2-[[2-[4-fluoro-3-(trifluoromethoxy)phenyl]-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]-3,5-dimethylphenyl]-5,5-dimethylimidazolidine-2,4-dione	EC50	5800 nM	US-9428505: Hydantoin derivative
1-[4-[2-[[2-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]-3,5-dimethylphenyl]-5,5-dimethylimidazolidine-2,4-dione	EC50	7200 nM	US-9428505: Hydantoin derivative
1-[4-[2-[[2-[3-fluoro-4-(trifluoromethoxy)phenyl]-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]-3,5-dimethylphenyl]-5,5-dimethylimidazolidine-2,4-dione	EC50	7400 nM	US-9428505: Hydantoin derivative
1-[4-[2-[[2-(2,2-difluoro-1,3-benzodioxol-5-yl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]-3,5-dimethylphenyl]-5,5-dimethylimidazolidine-2,4-dione	EC50	8100 nM	US-9428505: Hydantoin derivative
1-[3,5-dimethyl-4-[2-[[4-oxo-2-[3-(trifluoromethyl)phenyl]-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]phenyl]-5,5-dimethylimidazolidine-2,4-dione	EC50	9000 nM	US-9428505: Hydantoin derivative
3-[4-[2-[[2-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]-3,5-dimethylphenyl]imidazolidine-2,4-dione	EC50	9000 nM	US-9428505: Hydantoin derivative
4-[3,5-dimethyl-4-[2-[[4-oxo-2-[4-(trifluoromethoxy)phenyl]-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]phenyl]-4,6-diazaspiro[2.4]heptane-5,7-dione	EC50	11000 nM	US-9428505: Hydantoin derivative
1-[3,5-dimethyl-4-[2-[[4-oxo-2-[4-(trifluoromethoxy)phenyl]-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]phenyl]-8-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione	EC50	12000 nM	US-9428505: Hydantoin derivative
3-[3,5-dimethyl-4-[2-[[4-oxo-2-[3-(trifluoromethoxy)phenyl]-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]phenyl]imidazolidine-2,4-dione	EC50	13000 nM	US-9428505: Hydantoin derivative
1-[4-[2-[[2-(3-bromophenyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]-3,5-dimethylphenyl]-5,5-dimethylimidazolidine-2,4-dione	EC50	14000 nM	US-9428505: Hydantoin derivative
5-[3,5-dimethyl-4-[2-[[4-oxo-2-[4-(trifluoromethoxy)phenyl]-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]phenyl]-2-oxa-5,7-diazaspiro[3.4]octane-6,8-dione	EC50	21000 nM	US-9428505: Hydantoin derivative
1-[4-[2-[[2-(4-ethylcyclohexyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]-3-methylphenyl]-5-methylimidazolidine-2,4-dione	EC50	25000 nM	US-9428505: Hydantoin derivative
1-[4-[2-[[2-(4-ethylcyclohexyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]-3-methylphenyl]-5,5-dimethylimidazolidine-2,4-dione	EC50	32000 nM	US-9428505: Hydantoin derivative

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Calcitriol	affects cotreatment, decreases expression, decreases secretion, affects chemical synthesis, affects expression	20
Calcium Carbonate	affects expression, decreases expression	6
Calcium	affects cotreatment, decreases expression, affects metabolic processing, increases abundance	4
maxacalcitol	decreases expression, decreases secretion	3
Cinacalcet	affects cotreatment, decreases expression	3
Cholecalciferol	affects cotreatment, decreases expression	3
Lithium	increases expression	3
Vitamin D	decreases expression, affects cotreatment	3
paricalcitol	decreases expression, decreases secretion	2
Phosphates	decreases reaction, decreases uptake, increases reaction, increases expression	2
Lithium Carbonate	increases expression	2
trichostatin A	affects expression, decreases reaction	1
vanadyl sulfate	decreases expression	1
N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide	decreases reaction, decreases uptake	1
bisindolylmaleimide I	decreases reaction, decreases uptake	1
seocalcitol	decreases expression	1
CGP 52608	increases reaction, affects binding	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, decreases uptake	1
1,25-dihydroxyvitamin D	decreases expression	1
Aluminum	affects binding, decreases secretion, increases uptake	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Dexamethasone	decreases expression, decreases reaction, increases expression	1
Estradiol	increases expression	1
Hydrochloric Acid	decreases secretion	1
Nickel	affects expression, decreases reaction	1
Phenytoin	increases expression	1
Smoke	decreases expression	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
24,25-Dihydroxyvitamin D 3	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01222026	PHASE4	COMPLETED	Systematic Treatment After Successful Surgical Treatment for Primary Hyperparathyroidism With Strontium Ranelate
NCT01306656	PHASE4	COMPLETED	Vitamin D Repletion in Primary Hyperparathyroidism
NCT01558115	PHASE4	TERMINATED	Denosumab in Primary Hyperparathyroidism
NCT03935984	PHASE4	RECRUITING	Calcitonin Pre-treatment to Improve SPECT-CT Sensitivity
NCT04085419	PHASE4	UNKNOWN	Osteoporosis in Primary Hyperparathyroidism
NCT06859580	PHASE4	RECRUITING	Bisphosphonate Prior to Parathyroidectomy in Primary Hyperparathyroidism
NCT01460030	PHASE3	COMPLETED	An Intra-individual Titration Study of KRN1493 for the Treatment of Hypercalcemia in Patients With Parathyroid Carcinoma or Intractable Primary Hyperparathyroidism
NCT03027557	PHASE3	COMPLETED	Treatment of Primary Hyperparathyroidism With Denosumab and Cinacalcet.
NCT03280264	PHASE3	COMPLETED	Phase 3 Study of KHK7580 for the Treatment of Hypercalcemia in Patients With Parathyroid Carcinoma or Primary Hyperparathyroidism
NCT00973336	PHASE2	UNKNOWN	Primary Hyperparathyroidism: Does a Systematic Treatment Improve the Calcium and Bone Metabolism After Surgery?
NCT01783002	PHASE2	UNKNOWN	11C Methionine PET for the Detection of Hyperfunctional Parathyroid Tissues
NCT03774771	PHASE2	COMPLETED	Safety, Pharmacokinetics, and Clinical Effects of Cinacalcet (AMG 073) in Primary Hyperparathyroidism
NCT03776058	PHASE2	COMPLETED	Safety, Tolerability, and Clinical Effects of Twice-daily Doses of Cinacalcet (AMG 073) in Adults With Primary Hyperparathyroidism (HPT)
NCT01598727	PHASE1	COMPLETED	Near Infrared Fluorescent Imaging in Thyroid and Parathyroid Surgery With the Fluobeam(TM) System of Fluoptics
NCT01996072	PHASE1	COMPLETED	EC17 for Intraoperative Imaging for Parathyroidectomy
NCT04844164	PHASE1	COMPLETED	Vitamin D Metabolism in Patients With Endocrine Disorders
NCT00674154	PHASE2/PHASE3	COMPLETED	Effect of Vitamin D Treatment in Primary Hyperparathyroidism
NCT01329666	PHASE2/PHASE3	WITHDRAWN	Primary Hyperparathyroidism (PHPT): Early Effect of Vitamin D
NCT02525796	PHASE2/PHASE3	COMPLETED	Evaluating Alternative Medical Therapies in Primary Hyperparathyroidism
NCT07444723	PHASE2/PHASE3	RECRUITING	Accuracy of 18F-Fluorocholine PET/MR and NeuroEXPLORER PET/CT Imaging for Localization of Parathyroid Tumors
NCT00432939	Not specified	COMPLETED	Primary Hyperparathyroidism: Non-classical Manifestations
NCT00522028	Not specified	COMPLETED	Asymptomatic Primary Hyperparathyroidism: A Prospective, Randomized Trial
NCT00877981	Not specified	COMPLETED	Open Versus Video-Assisted Minimal-Invasive Parathyroid Surgery
NCT00961701	Not specified	TERMINATED	Lipids Profile in Primary Hyperparathyroidism
NCT00982722	Not specified	COMPLETED	Vitamin D Supplementation After Parathyroid Surgery
NCT01057732	Not specified	COMPLETED	Effects of Parathyroidectomy on Cardiovascular Risk Factors in Primary Hyperparathyroidism
NCT01087619	Not specified	COMPLETED	Surgery for Primary Hyperparathyroidism (pHPT) in Patients Older Than 65 Years Compared With Follow-up
NCT01228786	Not specified	UNKNOWN	Regulation of Vitamin D Receptor (VDR),Calcium Sensing Receptor (CaSR), Cyclin D1,Ki67 and Proliferating Cell Nuclear Antigen (PCNA) in Primary Hyperparathyroidism
NCT01409798	Not specified	COMPLETED	The Midwest Head and Neck Cancer Consortium Multi-Institutional Parathyroid Registry
NCT01530919	Not specified	COMPLETED	Minimally Invasive Radioguided Parathyroidectomy
NCT01571843	Not specified	COMPLETED	Radius Loading in Primary Hyperparathyroidism
NCT01647503	Not specified	UNKNOWN	Differentially Expressed Proteins in Sporadic Parathyroid Tumors
NCT01776502	Not specified	COMPLETED	Evaluation of Non Specific Symptoms and Quality of Life Before and After Surgery for Mild Primary Hyperparathyroidism
NCT01889134	Not specified	COMPLETED	OPG/Soluble RANKL (sRANKL) and Bone Mineral Density in Primary Hyperparathyroidism
NCT02227264	Not specified	COMPLETED	Primary Hyperparathyroidism: Short-term Calcimimetics Treatment - Relevance for Parathyroid Surgery Decisions?
NCT02539498	Not specified	COMPLETED	Bone Architectural Parameters in Postmenopausal Women Affected With Primary Hyperparathyroidism
NCT02854345	Not specified	COMPLETED	Preliminary Study Concerning the Validity of Parathyroid Exploration on a CZT Camera
NCT02989428	Not specified	COMPLETED	Effect of Parathyroidectomy on Cardiovascular Health
NCT03011736	Not specified	COMPLETED	Omission of Intact Parathyroid Hormone Testing During Surgery in Treating Patients With Primary Hyperparathyroidism
NCT03039439	Not specified	RECRUITING	Molecular and Immunohistochemical Profiling of Tumors in Patients With Parathyroid Tumors