P2RX2

Summary

P2RX2 (purinergic receptor P2X 2, HGNC:15459) is a protein-coding gene on chromosome 12q24.33, encoding P2X purinoceptor 2 (Q9UBL9). ATP-gated nonselective transmembrane cation channel permeable to potassium, sodium and calcium.

The product of this gene belongs to the family of purinoceptors for ATP. This receptor functions as a ligand-gated ion channel. Binding to ATP mediates synaptic transmission between neurons and from neurons to smooth muscle. Multiple transcript variants encoding distinct isoforms have been identified for this gene.

Source: NCBI Gene 22953 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant nonsyndromic hearing loss 41 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 341 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 5
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_170682

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15459
Approved symbol	P2RX2
Name	purinergic receptor P2X 2
Location	12q24.33
Locus type	gene with protein product
Status	Approved
Aliases	P2X2
Ensembl gene	ENSG00000187848
Ensembl biotype	protein_coding
OMIM	600844
Entrez	22953

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 8 protein_coding

ENST00000343948, ENST00000348800, ENST00000350048, ENST00000351222, ENST00000352418, ENST00000449132, ENST00000542301, ENST00000643471

RefSeq mRNA: 8 — MANE Select: NM_170682 NM_001282164, NM_001282165, NM_012226, NM_016318, NM_170682, NM_170683, NM_174872, NM_174873

CCDS: CCDS31930, CCDS31931, CCDS31932, CCDS31933, CCDS31934, CCDS31935, CCDS61286, CCDS73548

Canonical transcript exons

ENST00000643471 — 11 exons

Exon	Start	End
ENSE00001365902	132621619	132622388
ENSE00001367825	132620445	132620583
ENSE00001368801	132620000	132620096
ENSE00001372898	132621475	132621540
ENSE00001373821	132621001	132621131
ENSE00001376167	132619844	132619919
ENSE00001383718	132619679	132619750
ENSE00001385767	132621255	132621345
ENSE00003661449	132620267	132620347
ENSE00003684890	132619439	132619574
ENSE00003820430	132618776	132618989

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 83.14.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0697 / max 10.3185, expressed in 32 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128827	0.0697	32

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	83.14	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	77.59	gold quality
right lung	UBERON:0002167	77.45	gold quality
lower esophagus muscularis layer	UBERON:0035833	76.76	gold quality
lower esophagus	UBERON:0013473	76.56	gold quality
right uterine tube	UBERON:0001302	75.38	gold quality
esophagus	UBERON:0001043	72.03	gold quality
lower esophagus mucosa	UBERON:0035834	71.56	gold quality
prostate gland	UBERON:0002367	70.19	gold quality
caput epididymis	UBERON:0004358	70.14	gold quality
biceps brachii	UBERON:0001507	69.26	gold quality
cauda epididymis	UBERON:0004360	69.24	gold quality
corpus epididymis	UBERON:0004359	69.15	gold quality
esophagus mucosa	UBERON:0002469	68.49	gold quality
small intestine Peyer’s patch	UBERON:0003454	65.73	gold quality
Ammon’s horn	UBERON:0001954	65.35	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	65.21	gold quality
spleen	UBERON:0002106	64.95	gold quality
small intestine	UBERON:0002108	64.66	gold quality
upper lobe of left lung	UBERON:0008952	64.40	gold quality
esophagus squamous epithelium	UBERON:0006920	64.22	gold quality
amygdala	UBERON:0001876	63.83	gold quality
metanephros cortex	UBERON:0010533	63.78	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	63.20	gold quality
epithelium of esophagus	UBERON:0001976	62.39	gold quality
upper lobe of lung	UBERON:0008948	62.33	gold quality
cranial nerve II	UBERON:0000941	61.48	silver quality
transverse colon	UBERON:0001157	61.28	gold quality
mucosa of transverse colon	UBERON:0004991	61.24	gold quality
secondary oocyte	CL:0000655	61.02	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.72

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting P2RX2, 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-23B-5P	99.98	66.07	587
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-7974	99.24	65.48	1137
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-10B-3P	99.04	66.98	988
HSA-MIR-3164	99.02	68.39	1071
HSA-MIR-6820-3P	99.02	68.50	1035
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-6819-5P	97.96	66.59	1071
HSA-MIR-6737-5P	97.75	66.54	1044
HSA-MIR-1285-3P	97.72	67.02	1932
HSA-MIR-5189-5P	97.72	66.96	1814
HSA-MIR-6812-5P	97.56	65.39	1059
HSA-MIR-6857-3P	96.70	65.43	915
HSA-MIR-4529-3P	96.40	66.46	582
HSA-MIR-6742-5P	96.32	64.01	869
HSA-MIR-4740-5P	96.25	67.96	726
HSA-MIR-1269A	92.75	64.61	542
HSA-MIR-1269B	92.75	64.73	538

Literature-anchored findings (GeneRIF, showing 36)

• The locus designated DFNA41 maps to a 15 cM region on chromosome 12q24.32-qter, proximal to the marker D12S1609. (PMID:12161595)
• Whole-cell voltage clamp recordings functionally correlated immunolocalisation of ATP-gated ion channels in isolated hair cells and supporting cells. P2X immunoreactivity was widespread throughout the epithelial lining of the cochlea. (PMID:12395104)
• Data provide biochemical evidence that in addition to the rapidly desensitising P2X1 and P2X3 receptors, the slowly desensitising subtypes P2X2, P2X4, and P2X5 are trimers of identical subunits. (PMID:15313628)
• Effect of acute hypoxia on cloned homo- and heteromeric P2X2 receptors expressed in human embryonic kidney 293 cells. (PMID:15331767)
• P2X(2) receptors are trimers, whereas the P2X(6) receptor subunits do not form stable oligomers (PMID:15657042)
• support a common site of ATP action at P2X receptors and suggest that non-conserved residues also play a regulatory role in agonist action (PMID:18487206)
• VILIP1 constitutively binds to P2X2 receptors and displays enhanced interactions in an activation- and calcium-dependent manner owing to exposure of its binding segment in P2X2 receptors (PMID:18922787)
• Specimens (12/15) from patients with spinal cord lesions and specimens (8/11) demonstrated strong staining for P(2)X(2) receptors in the detrusor muscle and the urothelium. (PMID:19104511)
• Intracellular cysteine430 residue mediates the potentiation of P2X2 receptor activity by reactive oxygen species. (PMID:19793987)
• Data suggest that interactions between alpha3beta4 nAChRs and P2X2 receptors may modulate transmission at enteric synapses that use ATP and acetylcholine as co-transmitters. (PMID:20426799)
• Lipid raft association and cholesterol sensitivity of P2X1-4 receptors for ATP (PMID:20699225)
• GABA(A) receptor dynamics are regulated by interaction with purinergic P2X(2) receptors (PMID:21343285)
• analysis of agonists trapped in ATP-binding sites of the P2X2 receptor (PMID:21576497)
• Studies indicate that P2X1, P2X2, and P2X4 receptors are detected in preglomerular microvessels. (PMID:21768526)
• one subunit of P2X2 and two subunits of P2X3 form P2X2/3 heteromeric receptors, whereas two subunits of P2X2 and one subunit of P2X6 constitute P2X2/6 receptors (PMID:22378790)
• High potency zinc modulation of human P2X2 receptors and low potency zinc modulation of rat P2X2 receptors share a common molecular mechanism (PMID:22556417)
• trimeric P2X receptors containing only two intact binding sites can be readily activated by ATP. (PMID:22828800)
• analysis of dominantly inherited, progressive sensorineural hearing loss DFNA41 in a six-generation kindred revealed a rare heterozygous allele, P2RX2 c.178G > T (p.V60L), at chr12:133,196,029, which cosegregated with fully penetrant hearing loss (PMID:23345450)
• the contribution of the extracellular, transmembrane, and intracellular segments to recovery from desensitization (PMID:23740251)
• Data indicate that MgATP2- activates P2X1 and P2X3, but not P2X2 and P2X4 receptors. (PMID:23959888)
• Molecular analyses of P2RX2 identified a novel missense mutation. (PMID:24211385)
• Data indicate that the P2X2(I328C) receptor was activated by propyl-methanethiosulfonate (MTS) as effectively as by ATP. (PMID:24273165)
• A novel mutation in the P2RX2 gene was identified in a MELAS family. (PMID:25788561)
• Results demonstrate that the stoichiometry of the heterotrimeric hP2X2/3 receptor is not fixed, but determined by the relative availability of P2X2 and P2X3 subunits (PMID:26184350)
• The results from this study demonstrate that there is a significant difference in the expression of the purinergic P2X2, P2X3 and P2X7 receptors in the different histological layers of the human urinary bladder. (PMID:26253104)
• Data show that monoclonal antibodies directed against human P2X3 (12D4) potentiated the slow inactivating current mediated by the heteromeric purinergic receptor hP2X2/3 channel. (PMID:27129281)
• These findings indicate that the CaMKII-mediated GluA1 phosphorylation of S567 and S831 is critical for P2X2-mediated AMPAR internalization and ATP-driven synaptic depression. (PMID:27624155)
• identified P2RX2, KCNQ5, ERBB3 and SOCS3 to be associated with the progression of age-related hearing impairment (PMID:29325454)
• Progressive Dominant Hearing Loss (Autosomal Dominant Deafness-41) and P2RX2 Gene Mutations: A Phenotype-Genotype Study. (PMID:31593348)
• A study of 3 hearing loss mutations in hP2X2 receptors that found while D273Y results in nonfunctional channels, V60L and G353R are conductive channels with diminished response to ATP, revealing the importance of full-strength activation of hP2X2 receptors in hearing protection. (PMID:31636190)
• Identification of a distinct desensitisation gate in the ATP-gated P2X2 receptor. (PMID:31843194)
• Generation and characterization of a P2rx2 V60L mouse model for DFNA41. (PMID:33791800)
• Increased P2x2 receptors induced by amyloid-beta peptide participates in the neurotoxicity in alzheimer’s disease. (PMID:34343896)
• Identification of a Novel Stop Loss Mutation in P2RX2 Gene in an Iranian Family with Autosomal Nonsyndromic Hearing Loss (PMID:34425661)
• P2X2 receptor subunit interfaces are missense variant hotspots, where mutations tend to increase apparent ATP affinity. (PMID:35285517)
• Identification of Calcium Channel-Related Gene P2RX2 for Prognosis and Immune Infiltration in Prostate Cancer. (PMID:36246559)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	p2rx2	ENSDARG00000002300
mus_musculus	P2rx2	ENSMUSG00000029503
rattus_norvegicus	P2rx2	ENSRNOG00000037456

Paralogs (6): P2RX5 (ENSG00000083454), P2RX7 (ENSG00000089041), P2RX6 (ENSG00000099957), P2RX1 (ENSG00000108405), P2RX3 (ENSG00000109991), P2RX4 (ENSG00000135124)

Protein

Protein identifiers

P2X purinoceptor 2 — Q9UBL9 (reviewed: Q9UBL9)

Alternative names: ATP receptor, Purinergic receptor

All UniProt accessions (2): Q9UBL9, Q32MC3

UniProt curated annotations — full annotation on UniProt →

Function. ATP-gated nonselective transmembrane cation channel permeable to potassium, sodium and calcium. Activation by extracellular ATP induces a variety of cellular responses, such as excitatory postsynaptic responses in sensory neurons, neuromuscular junctions (NMJ) formation, hearing, perception of taste and peristalsis. In the inner ear, regulates sound transduction and auditory neurotransmission, outer hair cell electromotility, inner ear gap junctions, and K(+) recycling. Mediates synaptic transmission between neurons and from neurons to smooth muscle.

Subunit / interactions. Homotrimer and heterotrimer; functional P2XRs are organized as homomeric and heteromeric trimers. Homotrimer. Forms heterotrimer with P2RX1. Forms heterotrimer with P2RX6. Forms heterotrimer with P2RX3.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in both the central and peripheral nervous system, as well as in the pituitary gland.

Disease relevance. Deafness, autosomal dominant, 41 (DFNA41) [MIM:608224] A form of non-syndromic deafness characterized by onset of progressive sensorineural hearing loss usually in the second decade. The hearing loss is severe and ultimately affects all frequencies. Exposure to noise exacerbates the hearing loss, particularly at high frequencies. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Fast activation by external ATP. Exhibits slow desensitization during prolonged ATP activation. Not sensitive to the ATP agonist:alpha/beta-methylene-ATP.

Similarity. Belongs to the P2X receptor family.

Isoforms (7)

UniProt ID	Names	Canonical?
Q9UBL9-1	A	yes
Q9UBL9-2	B
Q9UBL9-3	C
Q9UBL9-4	D
Q9UBL9-5	H
Q9UBL9-6	I
Q9UBL9-7	K

RefSeq proteins (8): NP_001269093, NP_001269094, NP_036358, NP_057402, NP_733782, NP_733783, NP_777361, NP_777362 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001429	P2X_purnocptor	Family
IPR003045	P2X2_purnocptor	Family
IPR027309	P2X_extracellular_dom_sf	Homologous_superfamily
IPR053792	P2X_RECEPTOR_CS	Conserved_site
IPR059116	P2X_receptor	Family

Pfam: PF00864

Catalyzed reactions (Rhea), 3 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (35 total): binding site 7, disulfide bond 6, splice variant 6, topological domain 3, glycosylation site 3, transmembrane region 2, sequence variant 2, sequence conflict 2, region of interest 2, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
9UWW	ELECTRON MICROSCOPY	2.19
9UWX	ELECTRON MICROSCOPY	2.41
9UWY	ELECTRON MICROSCOPY	2.48
9DDW	ELECTRON MICROSCOPY	2.49
9DDX	ELECTRON MICROSCOPY	2.55
9OM0	ELECTRON MICROSCOPY	2.58
9OJK	ELECTRON MICROSCOPY	2.6
9ON5	ELECTRON MICROSCOPY	2.6
9ON6	ELECTRON MICROSCOPY	2.6
9UX3	ELECTRON MICROSCOPY	2.64
9OMR	ELECTRON MICROSCOPY	2.68
9OGH	ELECTRON MICROSCOPY	2.7
9DDV	ELECTRON MICROSCOPY	2.71
9UX2	ELECTRON MICROSCOPY	2.73
9Z32	ELECTRON MICROSCOPY	2.83
9UX1	ELECTRON MICROSCOPY	2.98
9OIR	ELECTRON MICROSCOPY	3
9OHK	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBL9-F1	80.80	0.55

Functional residue map

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

Ligand- & substrate-binding residues (7): 196; 296; 300; 302; 319; 81; 83

Disulfide bonds (6): 21–439, 125–176, 136–159, 142–170, 226–236, 270–279

Glycosylation sites (3): 133, 194, 310

Mutagenesis-validated functional residues (1):

Position	Phenotype
273	abolishes localization on the cell membrane.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-139853	Elevation of cytosolic Ca2+ levels
R-HSA-418346	Platelet homeostasis

MSigDB gene sets: 168 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_BEHAVIOR, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOCC_SECRETORY_GRANULE, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_SENSORY_PERCEPTION_OF_CHEMICAL_STIMULUS, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_MULTICELLULAR_ORGANISMAL_RESPONSE_TO_STRESS

GO Biological Process (22): response to hypoxia (GO:0001666), response to ischemia (GO:0002931), detection of hypoxic conditions in blood by carotid body chemoreceptor signaling (GO:0003029), neuromuscular synaptic transmission (GO:0007274), neuromuscular junction development (GO:0007528), sensory perception of sound (GO:0007605), response to carbohydrate (GO:0009743), positive regulation of calcium ion transport into cytosol (GO:0010524), urinary bladder smooth muscle contraction (GO:0014832), peristalsis (GO:0030432), response to ATP (GO:0033198), behavioral response to pain (GO:0048266), skeletal muscle fiber development (GO:0048741), positive regulation of calcium-mediated signaling (GO:0050850), sensory perception of taste (GO:0050909), calcium ion transmembrane transport (GO:0070588), monoatomic ion transport (GO:0006811), chemical synaptic transmission (GO:0007268), monoatomic ion transmembrane transport (GO:0034220), purinergic nucleotide receptor signaling pathway (GO:0035590), excitatory postsynaptic potential (GO:0060079), monoatomic cation transmembrane transport (GO:0098655)

GO Molecular Function (7): purinergic nucleotide receptor activity (GO:0001614), extracellularly ATP-gated monoatomic cation channel activity (GO:0004931), ATP binding (GO:0005524), ligand-gated monoatomic ion channel activity (GO:0015276), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), monoatomic ion channel activity (GO:0005216)

GO Cellular Component (8): plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), neuronal cell body (GO:0043025), signaling receptor complex (GO:0043235), postsynapse (GO:0098794), neuronal dense core vesicle (GO:0098992), membrane (GO:0016020), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Platelet calcium homeostasis	1
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to stress	2
response to oxygen-containing compound	2
cellular anatomical structure	2
response to decreased oxygen levels	1
detection of hypoxic conditions in blood by chemoreceptor signaling	1
regulation of systemic arterial blood pressure by carotid body chemoreceptor signaling	1
chemical synaptic transmission	1
synapse organization	1
sensory perception of mechanical stimulus	1
positive regulation of cytosolic calcium ion concentration	1
regulation of calcium ion transport into cytosol	1
calcium ion transport into cytosol	1
positive regulation of calcium ion transmembrane transport	1
urinary tract smooth muscle contraction	1
phasic smooth muscle contraction	1
response to purine-containing compound	1
response to organophosphorus	1
behavior	1
response to pain	1
skeletal muscle tissue development	1
myotube cell development	1
calcium-mediated signaling	1
regulation of calcium-mediated signaling	1
positive regulation of intracellular signal transduction	1
sensory perception of chemical stimulus	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
transport	1
anterograde trans-synaptic signaling	1
monoatomic ion transport	1
transmembrane transport	1
cell surface receptor signaling pathway	1
nucleotide receptor activity	1
purine nucleotide binding	1
purinergic nucleotide receptor signaling pathway	1
excitatory extracellular ligand-gated monoatomic ion channel activity	1
ATP-gated ion channel activity	1
ligand-gated monoatomic cation channel activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1

Protein interactions and networks

STRING

884 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
P2RX2	P2RX3	P56373	984
P2RX2	P2RX6	O15547	962
P2RX2	P2RX5	Q93086	948
P2RX2	P2RX4	Q99571	885
P2RX2	P2RY6	Q15077	873
P2RX2	P2RY4	P51582	863
P2RX2	P2RX1	P51575	813
P2RX2	P2RY2	P41231	811
P2RX2	P2RY11	Q96G91	763
P2RX2	A0A0B4J1V8	A0A0B4J1V8	738
P2RX2	P2RY14	Q15391	715
P2RX2	ZNF77	Q15935	712
P2RX2	P2RY1	P47900	710
P2RX2	PANX1	Q96RD7	705
P2RX2	P2RY13	Q9BPV8	701

IntAct

4 interactions, top by confidence:

A	B	Type	Score
P2RX2	C1QL1	psi-mi:“MI:0914”(association)	0.350
GXYLT1	P4HB	psi-mi:“MI:0914”(association)	0.350
P2RX2	TMEM131L	psi-mi:“MI:0914”(association)	0.350

BioGRID (88): KIAA1586 (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS), CANX (Affinity Capture-MS), C1QL1 (Affinity Capture-MS), EVI5L (Affinity Capture-MS), D2HGDH (Affinity Capture-MS), STARD3 (Affinity Capture-MS), P2RX2 (Affinity Capture-MS), FKBP7 (Affinity Capture-MS), HS2ST1 (Affinity Capture-MS), EPHB4 (Affinity Capture-MS), GALNT11 (Affinity Capture-MS), SPPL3 (Affinity Capture-MS), TUBB8 (Affinity Capture-MS), SLC25A46 (Affinity Capture-MS)

ESM2 similar proteins: A1L134, A4D1U4, A6NFY4, A7MB75, D3Z291, F1NNL1, O43292, O95870, P51571, P70295, Q0PGW2, Q0VF94, Q17RQ9, Q1JPD2, Q28DH9, Q2HJ63, Q2TBX5, Q3U128, Q3U284, Q3UHG7, Q3UX43, Q4R8P0, Q5FVM1, Q5HYA8, Q5NDE9, Q5NDF0, Q5NDF2, Q5R6S0, Q5RBT8, Q5REH6, Q5RJQ8, Q6DDX8, Q6MG55, Q8BJQ9, Q8BXQ2, Q8C1F4, Q8IU99, Q8J025, Q8TDX6, Q8VEC4

Diamond homologs: F8W463, O15547, O54803, O70397, P47824, P49653, P49654, P51575, P51576, P51577, P51578, P51579, P56373, Q3UR32, Q5E9U1, Q64663, Q8K3P1, Q91VE2, Q93086, Q99571, Q99572, Q9JJX6, Q9UBL9, Q9Z1M0, Q86JM7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	179
Likely benign	87
Benign	35

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
155762	NM_170682.4(P2RX2):c.178G>T (p.Val60Leu)	Pathogenic
155763	NM_170682.4(P2RX2):c.1057G>C (p.Gly353Arg)	Pathogenic
4082203	NM_170682.4(P2RX2):c.178G>C (p.Val60Leu)	Pathogenic
3340149	NM_170682.4(P2RX2):c.121dup (p.Leu41fs)	Likely pathogenic

SpliceAI

1667 predictions. Top by Δscore:

Variant	Effect	Δscore
12:132619553:GGA:G	donor_gain	1.0000
12:132619554:GAG:G	donor_gain	1.0000
12:132619556:G:GG	donor_gain	1.0000
12:132620265:A:AG	acceptor_gain	1.0000
12:132620266:G:GA	acceptor_gain	1.0000
12:132620266:GC:G	acceptor_gain	1.0000
12:132620266:GCC:G	acceptor_gain	1.0000
12:132620266:GCCA:G	acceptor_gain	1.0000
12:132620266:GCCAA:G	acceptor_gain	1.0000
12:132620348:G:GG	donor_gain	1.0000
12:132620530:C:G	donor_gain	1.0000
12:132620558:A:T	donor_gain	1.0000
12:132620995:T:TA	acceptor_gain	1.0000
12:132620995:TGGCA:T	acceptor_loss	1.0000
12:132620996:G:A	acceptor_gain	1.0000
12:132620996:GGCAG:G	acceptor_loss	1.0000
12:132620997:GCA:G	acceptor_loss	1.0000
12:132620998:CA:C	acceptor_loss	1.0000
12:132620999:A:AG	acceptor_gain	1.0000
12:132620999:A:G	acceptor_loss	1.0000
12:132620999:AG:A	acceptor_gain	1.0000
12:132620999:AGG:A	acceptor_gain	1.0000
12:132620999:AGGGT:A	acceptor_gain	1.0000
12:132621000:G:A	acceptor_gain	1.0000
12:132621000:G:GA	acceptor_gain	1.0000
12:132621000:GGG:G	acceptor_gain	1.0000
12:132621000:GGGT:G	acceptor_gain	1.0000
12:132621000:GGGTG:G	acceptor_gain	1.0000
12:132621119:GC:G	donor_gain	1.0000
12:132621127:TTCAG:T	donor_loss	1.0000

AlphaMissense

3080 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:132621030:G:C	W268C	1.000
12:132621030:G:T	W268C	1.000
12:132620065:T:A	W175R	0.999
12:132620065:T:C	W175R	0.999
12:132620067:G:C	W175C	0.999
12:132620067:G:T	W175C	0.999
12:132621028:T:A	W268R	0.999
12:132621028:T:C	W268R	0.999
12:132621061:T:A	C279S	0.999
12:132621062:G:C	C279S	0.999
12:132621131:G:T	R302M	0.999
12:132621292:C:A	R315S	0.999
12:132621293:G:C	R315P	0.999
12:132620017:T:A	C159S	0.998
12:132620018:G:C	C159S	0.998
12:132620050:T:A	C170S	0.998
12:132620051:G:C	C170S	0.998
12:132620068:T:A	C176S	0.998
12:132620069:G:C	C176S	0.998
12:132620315:C:A	N201K	0.998
12:132620315:C:G	N201K	0.998
12:132620515:T:C	C236R	0.998
12:132620516:G:A	C236Y	0.998
12:132620517:C:G	C236W	0.998
12:132621034:T:A	C270S	0.998
12:132621035:G:A	C270Y	0.998
12:132621035:G:C	C270S	0.998
12:132621036:T:G	C270W	0.998
12:132621061:T:C	C279R	0.998
12:132621320:G:C	R324P	0.998

dbSNP variants (sampled 300 via entrez): RS1000053191 (12:132617519 C>G,T), RS1000533137 (12:132617892 T>C), RS1001134980 (12:132620504 C>G,T), RS1002249416 (12:132621212 C>A,T), RS1002580420 (12:132621010 A>C,G,T), RS1003072004 (12:132622211 A>G), RS1003145893 (12:132622413 G>A,C), RS1003289007 (12:132617962 T>C), RS1003841351 (12:132616841 C>T), RS1003916757 (12:132617161 A>G), RS1004041420 (12:132622082 A>C,G), RS1005089014 (12:132616795 C>T), RS1005517365 (12:132618532 G>A,T), RS1005850083 (12:132620045 A>G), RS1006401732 (12:132621306 G>A,C)

Disease associations

OMIM: gene MIM:600844 | disease phenotypes: MIM:608224, MIM:124900

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant nonsyndromic hearing loss 41	Strong	Autosomal dominant
nonsyndromic genetic hearing loss	Moderate	Autosomal dominant
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Moderate	AD

Mondo (3): autosomal dominant nonsyndromic hearing loss 41 (MONDO:0011994), autosomal dominant nonsyndromic hearing loss (MONDO:0019587), nonsyndromic genetic hearing loss (MONDO:0019497)

Orphanet (1): Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000360	Tinnitus
HP:0000408	Progressive sensorineural hearing impairment
HP:0003621	Juvenile onset
HP:0025708	Early young adult onset

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005951_3	Body mass index	6.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C564272	Deafness, Autosomal Dominant 41 (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2531 (SINGLE PROTEIN), CHEMBL3831281 (PROTEIN COMPLEX), CHEMBL4524012 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 63,569 (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
CHEMBL3716057	GEFAPIXANT	4	386
CHEMBL265502	SURAMIN	3	36,848
CHEMBL82202	PYRIDOXAL PHOSPHATE ANHYDROUS	3	26,220
CHEMBL5095224	ELIAPIXANT	2	115

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — P2X receptors

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
NF770	Antagonist	8.0	pIC50
NF778	Antagonist	8.0	pIC50
PSB-10211	Antagonist	7.0	pIC50
ATP	Agonist	5.85	pEC50
suramin	Antagonist	4.98	pIC50

Binding affinities (BindingDB)

450 measured of 462 human assays (465 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
A-317491	KI	0.9 nM
ATP, 2-meS	KI	2.2 nM
NSC_0	KI	4.2 nM
NSC_175692	KI	4.6 nM
({({[5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)methylphosphoryl}oxy)phosphonic acid	KI	10.1 nM
NSC_440210	KI	13.6 nM
3-[(2- Methylpyridin- 4-yl)oxy]-5- (5-methyl- 1,3-thiazol-2- yl)-N-{(1R)-1- [2- (trifluorometh- yl)pyrimidin- 5- yl]ethyl} benzamide	IC50	14 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-(5-ethyl-1,3- thiazol-2-yl)-5- [(3R)- tetrahydrofuran-3- ylmethoxy]-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide	IC50	14 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
CAS_644357	KI	14.5 nM
N-[(1R)-1-(6- Methyl- pyridazin-3- yl)ethyl]-3- [(2- methylpyridin- 4-yl)oxy]-5- (5-methyl- 1,3-thiazol-2- yl)benzamide	IC50	16 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
NSC_123694	KI	16.1 nM
N-[(1R)-1-(6- Methylpyridin- 3-yl)ethyl]- 3-[(2- methylpyridin- 4-yl)oxy]-5- (5-methyl- 1,3-thiazol-2- yl)benzamide	IC50	17 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-(5-Methyl- 1,3-thiazol-2- yl)-5- (tetrahydro- 2H-pyran-4- ylmethoxy)- N-[(1R)-1-[2- (trifluorometh- yl)pyrimidin- 5- yl]ethyl] benzamide	IC50	19 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-(5-ethyl-1,3- thiazol-2-yl)-5- [(3R)- tetrahydrofuran-3- yloxy]-N-{(1R)-1- [2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide	IC50	22 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
NSC_0	KI	22.7 nM
3-(5-ethyl-1,3- thiazol-2-yl)-5- [(3S)- tetrahydrofuran-3- ylmethoxy]-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl} benzamide	IC50	23 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
NSC_440317	KI	24.4 nM
N-[(1R)-1-(6- Methyl- pyridazin-3- yl)ethyl]-3- (5-methyl- 1,3-thiazol-2- yl)-5- (tetrahydro- 2H-pyran-4- ylmethoxy) benzamide	IC50	27 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-(5-Ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide	IC50	27 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-{[1-(2,2- difluoroethyl) piperidin-4-yl]oxy}- 5-(5-methyl-1,3- thiazol-2-yl)-N- {(1R)-1-[2- (trifluoroethyl) pyrimidin-5- yl]ethyl}benzamide	IC50	27 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-{[4,4-difluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide	IC50	28 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-[(4,4-difluoro-1-methylpiperidin-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-[(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide	IC50	28 nM	US-10183937: 1,3-thiazol-2-yl substituted benzamides
3-(5-Ethyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide	IC50	33 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
N-[1-(5- Chloro-3- fluoropyridin- 2-yl)ethyl]-3- (5-methyl- 1,3-thiazol-2- yl)-5- (tetrahydro- 2H-pyran-4- yloxy) benzamide	IC50	34 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-(5-ethyl-1,3- thiazol-2-yl)-N- [(1R)-1-(6- methylpyridazin-3- yl)ethyl]-5-[(3R)- tetrahydrofuran-3- yloxy]benzamide	IC50	35 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-(5-ethyl-1,3- thiazol-2-yl)-5- [(2R)- tetrahydrofuran-2- ylmethoxy]-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide	IC50	35 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
N-[(1R)-1-(6- methylpyridazin-3- yl)ethyl]-3-(5- methyl-1,3- thiazol-2-yl)-5-{[1- (2,2,2- trifluoroethyl) piperidin-4-yl]oxy} benzamide	IC50	35 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-{[4,4- difluoro-1- methylpiperidin- 3-yl]methoxy}-5- (5-methyl-1,3- thiazol-2-yl)- N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl} benzamide, as a mixture of 2 diastereoisomers	IC50	35 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-(5-Methyl- 1,3-thiazol-2- yl)-5- (tetrahydro- 2H-pyran-4- yloxy)-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl} benzamide	IC50	36 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
N-[1-(5-Chloro-3-fluoropyridin-2-yl)ethyl]-3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzamide	IC50	38 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-(5-ethyl-1,3- thiazol-2-yl)-5- [(3S)- tetrahydrofuran-3- yloxy]-N-{(1R)-1- [2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide	IC50	38 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-(5-ethyl-1,3- thiazol-2-yl)-N- [(1R)-1-(6- methylpyridazin-3- yl)ethyl]-5-[(3R)- tetrahydrofuran-3- ylmethoxy] benzamide	IC50	38 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-(5-methyl-1,3- thiazol-2-yl)-5-{[1- (2,2,2- trifluoroethyl) piperidin-4-yl]oxy}- N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide	IC50	38 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-[(2- Methylpyridin- 4-yl)oxy]-5- (5-methyl- 1,3-thiazol-2- yl)-N-{(1R)-1- [6- (trifluorometh- yl)pyridazin- 3- yl]ethyl} benzamide	IC50	39 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-[(2-methylpyridin-4-yl)oxy]-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide	IC50	41 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-{[1-(2,2- difluoroethyl) piperidin-4-yl]oxy}-N- [(1R)-1-(6- methylpyridazin-3- yl)ethyl]-5-(5- methyl-1,3- thiazol-2-yl) benzamide	IC50	44 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-[(3-fluoro-1- methylpiperidin-4- yl)oxy]-5-(5- methyl-1,3- thiazol-2-yl)-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl} benzamide, as a single unknown isomer	IC50	46 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
dATP	KI	47.2 nM
3-(5-ethyl-1,3- thiazol-2-yl)-5- [(3R)- tetrahydrofuran-3- ylmethoxy]-N- {(1R)-1-[6- (trifluoromethyl) pyridazin-3-yl] ethyl}benzamide	IC50	52 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
CAS_123848	KI	53.8 nM
N-[1-(5- Chloro-3- fluoropyridin- 2-yl)ethyl]-3- (5-methyL- 1,3-thiazol-2- yl)-5-[(3S)- tetrahydrofuran- 3-ylmethoxy] benzamide	IC50	54 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
Ethyl (3S)-3-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]pyrrolidine-1-carboxylate	IC50	54 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
N-[(1R)-1-(5- Methylpyrazin- 2-yl)ethyl]- 3-[(2- methylpyridin- 4-yl)oxy]-5- (5-methyl- 1,3-thiazol-2- yl)benzamide	IC50	57 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-(5-ethyl-1,3- thiazol-2-yl)-N- [(1R)-1-(6- methylpyridazin-3- yl)ethyl]-5-[(3S)- tetrahydrofuran-3- yloxy]benzamide	IC50	57 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-(5-ethyl-1,3- thiazol-2-yl)-5- [(2S)- tetrahydrofuran-2- ylmethoxy]-N- {(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide	IC50	57 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
Methyl 4-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate	IC50	59 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
N-[(6- Methyl- pyridazin-3- yl)methyl]-3- [(2- methylpyridin- 4-yl)oxy]-5- (5-methyl- 1,3-thiazol-2- yl)benzamide	IC50	60 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-(5-ethyl-1,3- thiazol-2-yl)-5- (oxetan-3-yloxy)- N-{(1R)-1-[2- (trifluoromethyl) pyrimidin-5- yl]ethyl}benzamide	IC50	70 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-(5-ethyl-1,3- thiazol-2-yl)-N-[(6- methylpyridazin-3- yl)methyl]-5- (tetrahydro-2H- pyran-4- yloxy)benzamide	IC50	70 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides
3-{[1-(2,2- difluoroethyl)piperidin- 4-yl]oxy}-N- [(1R)-1-(2- methylpyrimidin- 5-yl)ethyl]-5-(5- methyl-1,3-thiazol-2- yl)benzamide	IC50	70 nM	US-10174016: 1,3-thiazol-2-yl substituted benzamides

ChEMBL bioactivities

2067 potent at pChembl≥5 of 2079 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.43	IC50	3.715	nM	CHEMBL5202979
8.42	Ki	3.802	nM	CHEMBL3715500
8.30	IC50	5.012	nM	CHEMBL494161
8.22	IC50	6	nM	CHEMBL3727382
8.15	IC50	7	nM	CHEMBL3730477
8.15	IC50	7	nM	CHEMBL3731764
8.10	Ki	7.943	nM	CHEMBL494161
8.08	IC50	8.318	nM	CHEMBL4583478
8.05	IC50	9	nM	CHEMBL3732909
8.05	Ki	9	nM	A-317491
8.00	IC50	10	nM	CHEMBL3732768
7.99	IC50	10.23	nM	CHEMBL3717153
7.96	IC50	11	nM	CHEMBL3729264
7.94	Ki	11.48	nM	CHEMBL495204
7.92	IC50	12	nM	CHEMBL3731419
7.92	IC50	12	nM	CHEMBL3731936
7.92	IC50	12	nM	CHEMBL3731399
7.90	IC50	12.59	nM	CHEMBL495204
7.89	IC50	13	nM	CHEMBL3728949
7.89	IC50	13	nM	CHEMBL3732959
7.86	Ki	13.8	nM	CHEMBL3718586
7.85	IC50	14	nM	CHEMBL3732309
7.85	IC50	14	nM	CHEMBL3732414
7.85	IC50	14	nM	CHEMBL3730913
7.85	IC50	14	nM	CHEMBL5975386
7.85	IC50	14	nM	CHEMBL5913570
7.82	IC50	15	nM	CHEMBL3731980
7.82	IC50	15	nM	CHEMBL3728821
7.82	IC50	15	nM	CHEMBL3727954
7.82	IC50	15	nM	CHEMBL3729987
7.82	IC50	15	nM	CHEMBL3730584
7.81	Ki	15.49	nM	CHEMBL3718862
7.81	Ki	15.49	nM	CHEMBL523173
7.80	IC50	16	nM	CHEMBL3728853
7.80	IC50	16	nM	CHEMBL3732382
7.80	IC50	16	nM	CHEMBL3730868
7.80	IC50	15.85	nM	CHEMBL492300
7.80	IC50	15.85	nM	CHEMBL523173
7.80	IC50	16	nM	CHEMBL5764480
7.79	Ki	16.22	nM	CHEMBL3718402
7.78	Ki	16.6	nM	CHEMBL492300
7.77	IC50	17	nM	CHEMBL3731399
7.77	IC50	17	nM	CHEMBL5815661
7.75	IC50	18	nM	CHEMBL3731366
7.72	IC50	19	nM	CHEMBL3729891
7.72	IC50	19	nM	CHEMBL3732843
7.72	IC50	19	nM	CHEMBL3728821
7.72	IC50	19	nM	CHEMBL5999082
7.71	IC50	19.6	nM	CHEMBL526307
7.70	IC50	20	nM	CHEMBL3731410

PubChem BioAssay actives

114 with measured affinity, of 370 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
[[(2R,3S,4R,5R)-5-(6-anilinopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	1870737: Agonist activity at human P2X2R expressing CHO cells assessed as reduction in intracellular Ca2+ influx pretreated with Fluo-4 for 1 hr followed by compound addition and further incubated for 30 mins in presence of ATP by multimode plate reader analysis	ic50	0.0037	uM
2-[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]propane-1,3-diol	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.0050	uM
[[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-sulfanylidene-3H-purin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	1870739: Agonist activity at human P2X2R/P2X3R expressing CHO cells assessed as reduction in intracellular Ca2+ influx pretreated with Fluo-4 for 1 hr followed by compound addition and further incubated for 30 mins in presence of ATP by multimode plate reader analysis	ic50	0.0083	uM
5-[(3-phenoxyphenyl)methyl-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]benzene-1,2,4-tricarboxylic acid	1627252: Antagonist activity at human P2X2/3 expressed in human1321N1 cells assessed as inhibition of alpha,beta-methylene-ATP-stimulated Ca2+ influx preincubated for 3 mins followed by alpha,beta-methylene-ATP addition measured after 3 mins by Fluo-4 assay	ki	0.0090	uM
5-(5-ethynyl-4-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine	417913: Antagonist activity at human recombinant P2X2/3 receptor expressed in human 1321N1 cells by FLIPR assay	ic50	0.0126	uM
2-[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]ethanol	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.0158	uM
2-[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]propan-1-ol	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.0158	uM
5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine	2111279: Antagonist activity at human P2X2/3R expressed in HEK293 cells incubated for 18 hrs by Fluo-4 dye based microplate reader assay	ic50	0.0196	uM
1-[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]propan-2-ol	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.0251	uM
(2R)-2-[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]propan-1-ol	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.0316	uM
3-[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]propane-1,2-diol	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.0316	uM
2-[[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]methyl]propane-1,3-diol	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.0316	uM
N-[2-[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]ethyl]acetamide	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.0398	uM
5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)-2-N-(2-methylsulfonylethyl)pyrimidine-2,4-diamine	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.0398	uM
2-[[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]methyl]-2-methylpropane-1,3-diol	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.0501	uM
[[(3aR,4R,6R,6aR)-4-(6-aminopurin-9-yl)-1’,3’,5’-trinitrospiro[3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxole-2,6’-cyclohexa-1,3-diene]-6-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	2111298: Antagonist activity at human P2X2/3 receptor assessed as reduction in calcium level incubated for 18 hrs by Fluo-4 AM dye based assay	ic50	0.0620	uM
5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)-2-N-(2-methoxyethyl)pyrimidine-2,4-diamine	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.0631	uM
3-[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]propan-1-ol	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.0631	uM
[[(3aR,4R,6R,6aR)-4-(6-aminopurin-9-yl)-1’,3’,5’-trinitrospiro[3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxole-2,6’-cyclohexa-1,4-diene]-6-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	1852202: Antagonist activity at human P2X2/3R transfected in CHO-K1 cells preincubated for 30 mins followed by alpha,beta-meATP addition by fluorescence based assay	ic50	0.0640	uM
5-(5-bromo-4-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine	417913: Antagonist activity at human recombinant P2X2/3 receptor expressed in human 1321N1 cells by FLIPR assay	ic50	0.0794	uM
[[(2R,3S,4R,5R)-5-(6-chloropurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	1870737: Agonist activity at human P2X2R expressing CHO cells assessed as reduction in intracellular Ca2+ influx pretreated with Fluo-4 for 1 hr followed by compound addition and further incubated for 30 mins in presence of ATP by multimode plate reader analysis	ic50	0.0871	uM
5-(5-chloro-4-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine	417913: Antagonist activity at human recombinant P2X2/3 receptor expressed in human 1321N1 cells by FLIPR assay	ic50	0.1000	uM
5-(5-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine	417913: Antagonist activity at human recombinant P2X2/3 receptor expressed in human 1321N1 cells by FLIPR assay	ic50	0.1585	uM
5-(5-ethyl-4-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine	417913: Antagonist activity at human recombinant P2X2/3 receptor expressed in human 1321N1 cells by FLIPR assay	ic50	0.1585	uM
3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-oxolan-3-yl]oxy-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide	2111302: Antagonist activity at human P2X2/3 receptor expressed in 1321N1 cells assessed as reduction in calcium level preincubated for 30 mins followed by alpha, beta-meATP addition by Fluo-4 AM dye based microplate reader assay	ic50	0.1630	uM
5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)-2-N-methylpyrimidine-2,4-diamine	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.1995	uM
5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)-2-N-(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.1995	uM
N-[(3,5-dichloro-4-hydroxyphenyl)carbamothioyl]-1,3-benzodioxole-5-carboxamide	1884355: Antagonist activity against human P2X2R stably transfected in human 1321N1 cells incubated for 30 mins by Fura-2 AM staining based calcium influx assay	ic50	0.2470	uM
2-N-[2-(dimethylamino)ethyl]-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.2512	uM
5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)-2-N-(2-piperazin-1-ylethyl)pyrimidine-2,4-diamine	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.2512	uM
[[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(methylamino)purin-9-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	1870739: Agonist activity at human P2X2R/P2X3R expressing CHO cells assessed as reduction in intracellular Ca2+ influx pretreated with Fluo-4 for 1 hr followed by compound addition and further incubated for 30 mins in presence of ATP by multimode plate reader analysis	ic50	0.2630	uM
[[(2R,3S,4R,5R)-3,4-dihydroxy-5-imidazo[2,1-f]purin-3-yloxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	1870739: Agonist activity at human P2X2R/P2X3R expressing CHO cells assessed as reduction in intracellular Ca2+ influx pretreated with Fluo-4 for 1 hr followed by compound addition and further incubated for 30 mins in presence of ATP by multimode plate reader analysis	ic50	0.2818	uM
5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)-2-N-(1-methylsulfonylpiperidin-4-yl)pyrimidine-2,4-diamine	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.3162	uM
5-(4-bromo-5-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine	417913: Antagonist activity at human recombinant P2X2/3 receptor expressed in human 1321N1 cells by FLIPR assay	ic50	0.3162	uM
5-(2,4-diaminopyrimidin-5-yl)oxy-2-methoxy-4-propan-2-ylbenzoic acid	417913: Antagonist activity at human recombinant P2X2/3 receptor expressed in human 1321N1 cells by FLIPR assay	ic50	0.3162	uM
5-[4-methoxy-2-propan-2-yl-5-(2H-tetrazol-5-yl)phenoxy]pyrimidine-2,4-diamine	417913: Antagonist activity at human recombinant P2X2/3 receptor expressed in human 1321N1 cells by FLIPR assay	ic50	0.3162	uM
[[(2R,3S,4R,5R)-4-amino-5-(6-aminopurin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	1870739: Agonist activity at human P2X2R/P2X3R expressing CHO cells assessed as reduction in intracellular Ca2+ influx pretreated with Fluo-4 for 1 hr followed by compound addition and further incubated for 30 mins in presence of ATP by multimode plate reader analysis	ic50	0.3631	uM
5-(4-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine	417913: Antagonist activity at human recombinant P2X2/3 receptor expressed in human 1321N1 cells by FLIPR assay	ic50	0.3981	uM
5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)-2-N-(2-morpholin-4-ylethyl)pyrimidine-2,4-diamine	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.3981	uM
5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)-2-N-(oxan-4-yl)pyrimidine-2,4-diamine	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.3981	uM
5-(4-iodo-5-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine	417913: Antagonist activity at human recombinant P2X2/3 receptor expressed in human 1321N1 cells by FLIPR assay	ic50	0.3981	uM
5-(4-methoxy-5-methyl-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine	417913: Antagonist activity at human recombinant P2X2/3 receptor expressed in human 1321N1 cells by FLIPR assay	ic50	0.3981	uM
2-[[4-formyl-5-hydroxy-6-methyl-3-(phosphonooxymethyl)-2-pyridinyl]diazenyl]benzene-1,4-disulfonic acid	150150: The compound was evaluated for antagonist activity against recombinant rat P2X purinoceptor 2 (P2X2) receptor 10 uM	ic50	0.4000	uM
5-(4,5-dimethoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine	417913: Antagonist activity at human recombinant P2X2/3 receptor expressed in human 1321N1 cells by FLIPR assay	ic50	0.5012	uM
5-(2,4-diaminopyrimidin-5-yl)oxy-2-methoxy-4-propan-2-ylbenzenesulfonamide	2111304: Antagonist activity at human P2X2/3 receptor	ic50	0.5200	uM
5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)-2-N-(2-piperidin-1-ylethyl)pyrimidine-2,4-diamine	414333: Antagonist activity at human P2X2/3 receptor expressed in 1321n1c cells by FLIPR	ic50	0.6310	uM
5-[5-(1H-imidazol-2-yl)-4-methoxy-2-propan-2-ylphenoxy]pyrimidine-2,4-diamine	417913: Antagonist activity at human recombinant P2X2/3 receptor expressed in human 1321N1 cells by FLIPR assay	ic50	0.6310	uM
N-[(4-nitrophenyl)carbamothioyl]-1,3-benzodioxole-5-carboxamide	1884355: Antagonist activity against human P2X2R stably transfected in human 1321N1 cells incubated for 30 mins by Fura-2 AM staining based calcium influx assay	ic50	0.6340	uM
disodium;1-amino-4-[3-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]-4-sulfonatoanilino]-9,10-dioxoanthracene-2-sulfonate	1358088: Antagonist activity at human P2X2 receptor expressed in 1321N1 cells assessed as inhibition of ATP-induced calcium flux measured for 30 secs at 0.4 secs intervals by Flou-4-AM dye based fluorescence assay	ic50	0.6900	uM
[[(2R,3S,4R,5R)-5-[6-(butylamino)purin-9-yl]-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	1870739: Agonist activity at human P2X2R/P2X3R expressing CHO cells assessed as reduction in intracellular Ca2+ influx pretreated with Fluo-4 for 1 hr followed by compound addition and further incubated for 30 mins in presence of ATP by multimode plate reader analysis	ic50	0.6918	uM

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
bisphenol A	affects cotreatment, decreases expression	1
quercitrin	increases expression	1
A-317491	affects binding, decreases activity	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	increases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

96 unique, capped per target: 67 binding, 29 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1017978	Functional	Antagonist activity at P2X2 receptor up to 10 uM	Identification and SAR of novel diaminopyrimidines. Part 2: The discovery of RO-51, a potent and selective, dual P2X(3)/P2X(2/3) antagonist for the treatment of pain. — Bioorg Med Chem Lett
CHEMBL2400256	Binding	Activity at human recombinant purinergic P2X2 receptor expressed in Xenopus oocytes assessed as effect on ATP-induced activation at 3 uM by two-electrode voltage clamp technique relative to control	Synthesis and structure activity relationship of tetrahydroisoquinoline-based potentiators of GluN2C and GluN2D containing N-methyl-D-aspartate receptors. — J Med Chem

Cellosaurus cell lines

14 cell lines: 9 transformed cell line, 4 induced pluripotent stem cell, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A1MI	UMi028-A-1	Induced pluripotent stem cell	Male
CVCL_C0YF	B’SYS CHO P2X2	Spontaneously immortalized cell line	Female
CVCL_D6U1	HEK293 P2RX2(B)	Transformed cell line	Female
CVCL_D6U2	HEK293 P2RX2(B)+P2RX3	Transformed cell line	Female
CVCL_D9M0	Ubigene HEK293 P2RX2 KO	Transformed cell line	Female
CVCL_E2Y1	HEK293 P2RX2(B)V60L	Transformed cell line	Female
CVCL_E2Y2	HEK293 P2RX2(B)D273Y	Transformed cell line	Female
CVCL_E2Y3	HEK293 P2RX2(B)G353R	Transformed cell line	Female
CVCL_E2Y4	HEK293 P2RX2(B)V60L+P2RX3	Transformed cell line	Female
CVCL_E2Y5	HEK293 P2RX2(B)D273Y+P2RX3	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations