PTH2R

Summary

PTH2R (parathyroid hormone 2 receptor, HGNC:9609) is a protein-coding gene on chromosome 2q34, encoding Parathyroid hormone 2 receptor (P49190). This is a specific receptor for parathyroid hormone.

The protein encoded by this gene is a member of the G-protein coupled receptor 2 family. This protein is a receptor for parathyroid hormone (PTH). This receptor is more selective in ligand recognition and has a more specific tissue distribution compared to parathyroid hormone receptor 1 (PTHR1). It is activated only by PTH and not by parathyroid hormone-like hormone (PTHLH) and is particularly abundant in brain and pancreas. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5746 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 129 total — 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_005048

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9609
Approved symbol	PTH2R
Name	parathyroid hormone 2 receptor
Location	2q34
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000144407
Ensembl biotype	protein_coding
OMIM	601469
Entrez	5746

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000272847, ENST00000419079, ENST00000487472, ENST00000617735

RefSeq mRNA: 5 — MANE Select: NM_005048 NM_001309516, NM_001371905, NM_001371906, NM_001371907, NM_005048

CCDS: CCDS2383, CCDS82565

Canonical transcript exons

ENST00000272847 — 13 exons

Exon	Start	End
ENSE00001072910	208493264	208494506
ENSE00001072917	208406792	208407118
ENSE00003485206	208428201	208428303
ENSE00003499181	208444734	208444887
ENSE00003550792	208437537	208437647
ENSE00003550885	208489012	208489150
ENSE00003553920	208442364	208442461
ENSE00003566722	208481070	208481164
ENSE00003574667	208437760	208437881
ENSE00003586839	208450749	208450809
ENSE00003609284	208443348	208443537
ENSE00003619859	208490639	208490680
ENSE00003680211	208459895	208459961

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 92.14.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4555 / max 42.4650, expressed in 101 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
24917	0.3055	93
24918	0.1499	47

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
metanephros cortex	UBERON:0010533	92.14	gold quality
endothelial cell	CL:0000115	86.33	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.67	gold quality
adult mammalian kidney	UBERON:0000082	80.86	gold quality
secondary oocyte	CL:0000655	78.62	gold quality
islet of Langerhans	UBERON:0000006	73.83	gold quality
Brodmann (1909) area 9	UBERON:0013540	70.82	gold quality
prefrontal cortex	UBERON:0000451	70.55	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	69.40	gold quality
right frontal lobe	UBERON:0002810	69.32	gold quality
Brodmann (1909) area 23	UBERON:0013554	69.08	gold quality
middle temporal gyrus	UBERON:0002771	68.44	gold quality
primary visual cortex	UBERON:0002436	68.06	gold quality
kidney	UBERON:0002113	68.05	gold quality
ventricular zone	UBERON:0003053	66.62	gold quality
frontal cortex	UBERON:0001870	66.55	gold quality
neocortex	UBERON:0001950	65.82	gold quality
amygdala	UBERON:0001876	65.69	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	65.41	gold quality
cingulate cortex	UBERON:0003027	64.71	gold quality
cortex of kidney	UBERON:0001225	64.62	gold quality
anterior cingulate cortex	UBERON:0009835	64.49	gold quality
cerebral cortex	UBERON:0000956	64.00	gold quality
metanephros	UBERON:0000081	62.35	gold quality
minor salivary gland	UBERON:0001830	62.33	gold quality
pancreas	UBERON:0001264	62.21	gold quality
Brodmann (1909) area 10	UBERON:0013541	62.21	silver quality
occipital lobe	UBERON:0002021	61.03	gold quality
bone marrow cell	CL:0002092	60.65	silver quality
saliva-secreting gland	UBERON:0001044	60.64	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	4856.99
E-ANND-3	yes	4.65
E-GEOD-131882	no	5109.69

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SIX1

miRNA regulators (miRDB)

68 targeting PTH2R, 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-5011-5P	100.00	83.46	5820
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514

Literature-anchored findings (GeneRIF, showing 12)

• specific interactions within the ligand-receptor bimolecular complex mediate distinct postactivation responses of class II G protein- coupled receptors and provide novel insights into the physiological regulation of PTH2R activity (PMID:14988434)
• 6 SNPs in the PTH gene and 3 SNPs each in the PTHLH, PTHR1 and PTHR2 genes were investigated in relation to bone mineral density (PMID:18280230)
• The distribution of PTH2R-immunoreactive fibers in viscerosensory brain regions is similar to that reported in mouse and rat suggesting a similar role of the PTH2R in human as in rodents. (PMID:18459453)
• Different receptor subtype properties were used to demonstrate that residue 41 in PTH-1R, when either the native Leu or substituted by Ile or Met, can accommodate either Phe or Trp at position 23 of the ligand. (PMID:18539702)
• The results demonstrate that TIP39 and the PTH2R are expressed in the brain of primates in locations that suggest involvement in regulation of fear, anxiety, reproductive behaviors, release of pituitary hormones, and nociception. (PMID:19401215)
• PTH-receptors regulate norepinephrine release in human heart and kidney (PMID:21756942)
• Data suggest role for PTH2R signaling in postnatal growth plate development and subsequent bone mass acquisition; overexpression of human PTH2R in chondrocytes of transgenic mice has key consequences on postnatal development of endochondral skeleton. (PMID:23092913)
• Variation in the PTH2R gene (Chr2q34, rs897083) may contribute to the age-associated degenerative manifestations that develop at the lumbar spine (PMID:24378925)
• Authors report PTH2R as a gene that is disrupted in NSC. The disruption of the PTH2R gene may cause uncontrolled proliferation and differentiation of chondrocytes. (PMID:26044810)
• PTH2R and its ligand TIP39 regulate intracellular calcium and influence keratinocyte differentiation (PMID:27000502)
• expressed in the epidermis in Darier disease (PMID:28094886)
• Molecular insights into differentiated ligand recognition of the human parathyroid hormone receptor 2. (PMID:34353904)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pth2ra	ENSDARG00000006678
danio_rerio	pth2rb	ENSDARG00000021186
mus_musculus	Pth2r	ENSMUSG00000025946
rattus_norvegicus	Pth2r	ENSRNOG00000015259

Paralogs (42): CALCR (ENSG00000004948), GIPR (ENSG00000010310), ADGRA2 (ENSG00000020181), CALCRL (ENSG00000064989), GLP2R (ENSG00000065325), ADGRF5 (ENSG00000069122), ADGRL1 (ENSG00000072071), ADCYAP1R1 (ENSG00000078549), SCTR (ENSG00000080293), VIPR2 (ENSG00000106018), CRHR2 (ENSG00000106113), GHRHR (ENSG00000106128), ADGRD1 (ENSG00000111452), GLP1R (ENSG00000112164), ADGRG6 (ENSG00000112414), VIPR1 (ENSG00000114812), ADGRL2 (ENSG00000117114), CRHR1 (ENSG00000120088), ADGRB2 (ENSG00000121753), ADGRE5 (ENSG00000123146), ADGRE2 (ENSG00000127507), ADGRE3 (ENSG00000131355), ADGRB3 (ENSG00000135298), ADGRG7 (ENSG00000144820), ADGRL3 (ENSG00000150471), ADGRA3 (ENSG00000152990), ADGRF1 (ENSG00000153292), ADGRF4 (ENSG00000153294), ADGRG4 (ENSG00000156920), ADGRG5 (ENSG00000159618), PTH1R (ENSG00000160801), ADGRL4 (ENSG00000162618), EVA1C (ENSG00000166979), ADGRF3 (ENSG00000173567), ADGRG2 (ENSG00000173698), ADGRE1 (ENSG00000174837), ADGRD2 (ENSG00000180264), ADGRB1 (ENSG00000181790), ADGRG3 (ENSG00000182885), ADGRA1 (ENSG00000197177)

Protein

Protein identifiers

Parathyroid hormone 2 receptor — P49190 (reviewed: P49190)

All UniProt accessions (3): P49190, B4DFN8, H7C0B0

UniProt curated annotations — full annotation on UniProt →

Function. This is a specific receptor for parathyroid hormone. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. PTH2R may be responsible for PTH effects in a number of physiological systems. It may play a significant role in pancreatic function. PTH2R presence in neurons indicates that it may function as a neurotransmitter receptor.

Subunit / interactions. Binds to TIPF39/TIP39.

Subcellular location. Cell membrane.

Tissue specificity. Expressed abundantly in brain and pancreas. Also expressed in the testis.

Similarity. Belongs to the G-protein coupled receptor 2 family.

RefSeq proteins (5): NP_001296445, NP_001358834, NP_001358835, NP_001358836, NP_005039* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000832	GPCR_2_secretin-like	Family
IPR001879	GPCR_2_extracellular_dom	Domain
IPR017981	GPCR_2-like_7TM	Domain
IPR017983	GPCR_2_secretin-like_CS	Conserved_site
IPR036445	GPCR_2_extracell_dom_sf	Homologous_superfamily
IPR050332	GPCR_2	Family

Pfam: PF00002, PF02793

UniProt features (41 total): helix 10, topological domain 8, transmembrane region 7, strand 5, glycosylation site 4, turn 3, signal peptide 1, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7F16	ELECTRON MICROSCOPY	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49190-F1	72.53	0.30

Antibody-complex structures (SAbDab): 1 — 7F16

Functional residue map

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

Glycosylation sites (4): 51, 106, 116, 121

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: 106 (showing top): MODULE_64, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, MODULE_379, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION, MODULE_123, GOMF_PEPTIDE_RECEPTOR_ACTIVITY, AACTTT_UNKNOWN, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, MODULE_242, GOBP_TEMPERATURE_HOMEOSTASIS, YAGI_AML_WITH_11Q23_REARRANGED, GOBP_POSITIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, MODULE_104, GOBP_HOMEOSTATIC_PROCESS, BLALOCK_ALZHEIMERS_DISEASE_DN

GO Biological Process (5): cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-modulating G protein-coupled receptor signaling pathway (GO:0007188), positive regulation of cold-induced thermogenesis (GO:0120162), signal transduction (GO:0007165)

GO Molecular Function (6): parathyroid hormone receptor activity (GO:0004991), G protein-coupled peptide receptor activity (GO:0008528), peptide hormone binding (GO:0017046), transmembrane signaling receptor activity (GO:0004888), G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

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
G protein-coupled receptor activity	3
signal transduction	2
G protein-coupled receptor signaling pathway	2
adenylate cyclase activity	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
peptide receptor activity	1
hormone binding	1
signaling receptor activity	1
transmembrane signaling receptor activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

532 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PTH2R	PTH2	Q96A98	987
PTH2R	PTH	P01270	963
PTH2R	PTHLH	P12272	952
PTH2R	FZD5	Q13467	769
PTH2R	RAMP3	O60896	550
PTH2R	CTDSP2	O14595	496
PTH2R	RHO	P08100	493
PTH2R	IHH	Q14623	459
PTH2R	FRZB	Q92765	432
PTH2R	GHSR	Q92847	426
PTH2R	CTCFL	Q8NI51	422
PTH2R	CRISP2	P16562	414
PTH2R	NKPD1	Q17RQ9	401
PTH2R	SPAG11A	Q6PDA7	399
PTH2R	PKD2L1	Q9P0L9	387

IntAct

138 interactions, top by confidence:

A	B	Type	Score
HMG20A	PTH2R	psi-mi:“MI:0915”(physical association)	0.560
PTH2R	HMG20A	psi-mi:“MI:0915”(physical association)	0.560
PTH2R	DYNLT1	psi-mi:“MI:0915”(physical association)	0.560
PTH2R	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
PARD3	PTH2R	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	FRMPD4	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
PARD3B	PTH2R	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
SCRIB	PTH2R	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	PALS2	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	PTH2R	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	FRMPD2	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	APBA2	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	LIN7B	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	LIN7C	psi-mi:“MI:0407”(direct interaction)	0.440
PTH2R	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (116): HMG20A (Two-hybrid), DYNLT1 (Two-hybrid), PTH (Reconstituted Complex), GNL3L (Affinity Capture-MS), INTS2 (Affinity Capture-MS), ATP5G1 (Affinity Capture-MS), RNASEL (Affinity Capture-MS), ATP2B2 (Affinity Capture-MS), PRKDC (Affinity Capture-MS), AP5Z1 (Affinity Capture-MS), C17orf80 (Affinity Capture-MS), ATL3 (Affinity Capture-MS), SLC39A10 (Affinity Capture-MS), FPGS (Affinity Capture-MS), IMMT (Affinity Capture-MS)

ESM2 similar proteins: A0A084B9Z2, A0A0A2JY25, A0A0D1E6B3, A0A0R8YXT5, A0A142I738, A0A2I1CSG1, A0A2L0P0K0, A0A348HAY3, A1CIM4, B2KWI0, G1X9E2, G1X9H9, G1XJN1, G5EDW2, I1RLA6, O13780, O13880, O42579, O60353, P0DUT8, P13773, P31302, P31303, P31397, P49190, P70555, P78741, P9WEL3, P9WEU1, P9WEV3, Q05659, Q09460, Q0CRW7, Q0V6Q8, Q12256, Q2KI97, Q4D3E8, Q4G2T3, Q4WR17, Q54ET0

Diamond homologs: A0A2Z2U4G9, A6QP74, O35659, O42602, O42603, O46502, O62772, O95838, P23811, P25107, P25117, P25961, P30082, P30083, P32082, P32215, P32241, P32301, P34998, P34999, P35000, P35347, P35353, P41586, P41587, P41588, P41593, P43218, P43219, P43220, P47866, P47871, P47872, P48546, P48960, P49190, P50133, P70205, P70555, P97751

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
PTH	up-regulates	PTH2R	binding
PTH2	up-regulates	PTH2R	binding
“Tuberoinfundibular peptide of 39 residues”	“up-regulates activity”	PTH2R	“chemical activation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 87 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	6	60.1×	4e-08
Unblocking of NMDA receptors, glutamate binding and activation	6	57.2×	4e-08
Negative regulation of NMDA receptor-mediated neuronal transmission	6	57.2×	4e-08
Long-term potentiation	6	50.1×	7e-08
Assembly and cell surface presentation of NMDA receptors	10	44.5×	2e-12
Dopamine Neurotransmitter Release Cycle	5	43.5×	3e-06
Neurexins and neuroligins	11	38.0×	1e-12
Protein-protein interactions at synapses	7	32.6×	7e-08

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	76.1×	4e-16
protein localization to synapse	6	54.7×	1e-07
receptor clustering	7	52.0×	1e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	7	41.3×	5e-08
protein-containing complex assembly	9	12.2×	3e-06
cell-cell adhesion	10	12.1×	8e-07
regulation of small GTPase mediated signal transduction	5	8.6×	6e-03
chemical synaptic transmission	7	6.4×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	100
Likely benign	13
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
428590	NM_005048.4(PTH2R):c.473C>T (p.Ser158Phe)	Likely pathogenic

SpliceAI

2052 predictions. Top by Δscore:

Variant	Effect	Δscore
2:208428199:AGCT:A	acceptor_gain	1.0000
2:208428200:GCTG:G	acceptor_gain	1.0000
2:208428301:G:T	donor_gain	1.0000
2:208437878:AAAG:A	donor_loss	1.0000
2:208437879:AAGGT:A	donor_loss	1.0000
2:208437880:AGGTA:A	donor_loss	1.0000
2:208437881:GG:G	donor_loss	1.0000
2:208437882:G:GA	donor_loss	1.0000
2:208437883:T:G	donor_loss	1.0000
2:208442362:A:AG	acceptor_gain	1.0000
2:208442363:G:GA	acceptor_gain	1.0000
2:208442363:GCAA:G	acceptor_gain	1.0000
2:208443400:A:AG	acceptor_gain	1.0000
2:208443400:AT:A	acceptor_gain	1.0000
2:208443400:ATGCT:A	acceptor_gain	1.0000
2:208443401:T:G	acceptor_gain	1.0000
2:208443404:T:A	acceptor_gain	1.0000
2:208444885:GGG:G	donor_gain	1.0000
2:208444885:GGGGT:G	donor_loss	1.0000
2:208444886:GG:G	donor_gain	1.0000
2:208444886:GGG:G	donor_gain	1.0000
2:208444887:GG:G	donor_gain	1.0000
2:208444887:GGTA:G	donor_loss	1.0000
2:208444888:G:GG	donor_gain	1.0000
2:208444888:GTA:G	donor_loss	1.0000
2:208444889:TAAGA:T	donor_loss	1.0000
2:208406986:G:GT	donor_gain	0.9900
2:208428199:A:AG	acceptor_gain	0.9900
2:208428199:AGCTG:A	acceptor_gain	0.9900
2:208428200:G:GG	acceptor_gain	0.9900

AlphaMissense

3631 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:208437559:G:C	W67C	0.999
2:208437559:G:T	W67C	0.999
2:208437577:G:C	W73C	0.999
2:208437577:G:T	W73C	0.999
2:208437797:G:C	W109C	0.998
2:208437797:G:T	W109C	0.998
2:208444884:T:A	W284R	0.998
2:208444884:T:C	W284R	0.998
2:208459901:G:C	W307C	0.998
2:208459901:G:T	W307C	0.998
2:208437557:T:A	W67R	0.997
2:208437557:T:C	W67R	0.997
2:208437575:T:A	W73R	0.997
2:208437575:T:C	W73R	0.997
2:208437614:T:C	C86R	0.997
2:208437772:G:C	R101P	0.997
2:208437777:T:A	C103S	0.997
2:208437778:G:C	C103S	0.997
2:208442404:G:A	G151D	0.997
2:208490639:G:C	G406R	0.997
2:208437614:T:A	C86S	0.996
2:208437615:G:A	C86Y	0.996
2:208437615:G:C	C86S	0.996
2:208437616:C:G	C86W	0.996
2:208437845:C:G	C125W	0.996
2:208443415:A:C	S193R	0.996
2:208443417:C:A	S193R	0.996
2:208443417:C:G	S193R	0.996
2:208444791:T:A	W253R	0.996
2:208444791:T:C	W253R	0.996

dbSNP variants (sampled 300 via entrez): RS1000067888 (2:208385789 A>G), RS1000081177 (2:208481231 T>C,G), RS1000086345 (2:208472683 G>A), RS1000087646 (2:208410475 C>G), RS1000110466 (2:208364167 C>T), RS1000114987 (2:208410887 G>A), RS1000130847 (2:208422685 T>G), RS1000138076 (2:208363751 C>T), RS1000140484 (2:208384072 T>G), RS1000168793 (2:208473961 T>C), RS1000184550 (2:208438148 C>A,T), RS1000184947 (2:208383400 G>A), RS1000275041 (2:208434964 T>C), RS1000297326 (2:208392001 G>A), RS1000324688 (2:208480658 A>G)

Disease associations

OMIM: gene MIM:601469 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): syndromic intellectual disability (MONDO:0000508)

Orphanet (1): Rare genetic syndromic intellectual disability (Orphanet:183763)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001543_1	Lung cancer (asbestos exposure interaction)	2.000000e-06
GCST002337_75	Amyotrophic lateral sclerosis (sporadic)	3.000000e-06
GCST004703_12	Obsessive-compulsive disorder or autism spectrum disorder	9.000000e-06
GCST008958_3	Anthropometric traits	5.000000e-07
GCST009391_434	Metabolite levels	4.000000e-06
GCST010922_1	Hip bone mineral density and total body fat mass (bivariate analysis)	1.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004806	asbestos exposure measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0010385	phosphatidylcholine 38:3 measurement
EFO:0007702	hip bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105836 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Parathyroid hormone receptors

Most potent curated ligand interactions (26 total), top 25:

Ligand	Action	Affinity	Parameter
PTH-(1-34) (rat)	Full agonist	9.5	pIC50
TIP39	Full agonist	9.2	pIC50
TIP39	Full agonist	8.8	pIC50
TIP39-(7-39) (mouse)	Antagonist	8.2	pIC50
[125I][Nle8,21,Tyr34]PTH-(1-34)-NH2 (rat)	Full agonist	8.1	pKd
PTHrP-(1-21)/PTH-(22-34) (human)	Antagonist	8.0	pIC50
[Ile5,Trp23]PTHrP-(1-36) (human)	Full agonist	8.0	pIC50
teriparatide	Full agonist	7.8	pIC50
[Ile5,Trp23,Tyr36]PTHrP-(1-36)-NH2 (human)	Full agonist	7.7	pIC50
[His4, Tyr5, Trp6, His7]TIP39 (human)	Antagonist	7.61	pA2
[Trp23]PTHrP-(1-36) (human)	Full agonist	7.5	pIC50
[Trp23,Tyr36]PTHrP-(1-36)-NH2 (human)	Full agonist	7.4	pIC50
[Ile5,Trp23]PTHrP-(2-36) (human)	Full agonist	7.3	pIC50
[D-Trp12]PTH-(7-34) (bovine)	Antagonist	7.3	pIC50
[Ile5,Trp23]PTHrP-(3-36) (human)	Full agonist	7.2	pIC50
TIP39-(7-39) (human/bovine)	Antagonist	7.2	pIC50
[Ile5,Trp23]PTHrP-(5-36)	Antagonist	7.0	pIC50
[Ile5,Trp23]PTHrP-(5-36) (human)	Full agonist	7.0	pIC50
[D-Trp12,Tyr34]PTH-(7-34) (bovine)	Antagonist	6.9	pIC50
[Ile5,Trp23]PTHrP-(4-36) (human)	Full agonist	6.8	pIC50
PTHrP-(7-34) (human, rat, mouse)	Antagonist	6.7	pIC50
[His5]PTH-(1-34) (human)	Full agonist	6.6	pIC50
[Phe23]PTH-(1-34) (human)	Full agonist	6.3	pIC50
[Ile5]PTHrP-(1-36)	Full agonist	6.2	pIC50
PTHrP-(1-34) (human)	Full agonist	6.1	pIC50

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, increases mutagenesis, increases expression	3
bisphenol A	affects cotreatment, decreases methylation	1
potassium perchlorate	increases expression	1
beta-methylcholine	affects expression	1
fipronil	increases expression	1
CGP 52608	affects binding, increases reaction	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	decreases methylation	1
Estradiol	affects cotreatment, decreases expression	1
Progesterone	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases expression	1

ChEMBL screening assays

4 unique, capped per target: 2 functional, 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4031020	Functional	Antagonist activity at human PTH2 receptor expressed in rat Chem-1 cells assessed as inhibition of TIP-39 induced calcium flux at 10 uM by fluorescence assay	Discovery of Small Molecules Targeting the Synergy of Cardiac Transcription Factors GATA4 and NKX2-5. — J Med Chem
CHEMBL4883586	Binding	PRESTO-Tango GPCRome screening (PTH2R)	Data for DCP probe UCSF924

Cellosaurus cell lines

5 cell lines: 2 transformed cell line, 2 spontaneously immortalized cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0TQ	ACTOne PTHR2	Transformed cell line	Female
CVCL_H374	293/PTH2/CRE-Luc	Transformed cell line	Female
CVCL_KV71	cAMP Hunter CHO-K1 PTHR2 Gs/Gq	Spontaneously immortalized cell line	Female
CVCL_KY91	PathHunter CHO-K1 PTHR2 beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_LB25	PathHunter U2OS PTHR2 Total GPCR Internalization	Cancer cell line	Female

Clinical trials (associated diseases)

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