P2RY12
protein-codingpurinergic receptor P2Y12, the group of P2Y receptors
Gene summary
The product of this gene belongs to the family of G-protein coupled receptors. This family has several receptor subtypes with different pharmacological selectivity, which overlaps in some cases, for various adenosine and uridine nucleotides. This receptor is involved in platelet aggregation, and is a potential target for the treatment of thromboembolisms and other clotting disorders. Mutations in this gene are implicated in bleeding disorder, platelet type 8 (BDPLT8). Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jul 2013]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~47.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012354
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0012354
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012354
Submitter: ClinGen
P2RY12 was first reported in relation to autosomal recessive platelet-type bleeding disorder 8 in 2001 (Hollopeter G, et al., 2001, PMID: 11196645). At least six unique variants (one frameshift, and four missenses, 1 start loss) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least eight probands in six publications (PMIDs: 11196645; 24612435; 25428217; 12578987; 16194207; 37389831 and ClinVar: VCV002572656.1 and VCV002572166.2). Strikingly, at least one proband and the family members showed to carry a concomitant mutation in another receptor (PMID: 24612435), which suggested that the variability in the phenotypes may be due to unexplored concomitant common or rare variants in other platelet or hemostatic genes. This gene-disease relationship is supported by its biochemical function that P2Y12 receptor stimulation induced rapid activation of Rap1 (PMID: 16236484), expression A evidence that P2Y12 receptor is selectively expressed in platelets (PMID: 11196645), expression B evidence that reduced P2Y12 receptor expression in patients (PMID: 24612435 ), functional alteration in both patient (PMID: 12578987, 16194207) and non-patient cells (PMID: 24612435).In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Hemostasis Thrombosis GCEP on 08/26/2020. It was reevaluated on 04/02/2023 and on 01/25/2025. As a result of this reevaluation, the classification has been upgraded to definitive.
Inheritance Pattern: AR
Disease ID:MONDO:0012354
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012354
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012354
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:1060234
Submitter: ClinGen
P2RY12 was first reported in relation to autosomal dominant platelet disorder in 2007 (Remijn JA, et al., PMID: 17311506). At least seven unique missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least eight probands in six publications (PMIDs: 29117459, 17311506, 25567036, 19237732, 21937696, 36232816). This gene-disease relationship is supported by its biochemical function in the P2Y12 receptor stimulation induced rapid activation of Rap1 (PMID: 16236484), expression A evidence of P2Y12 receptor is selectively expressed in platelets (PMID: 11196645), expression B evidence of reduced P2Y12 receptor expression in patients ( PMID: 21937696), functional alteration in both patient ( PMID: 17311506) and non-patient cells ( PMID: 29117459, PMID: 23387322), and non-human model organism knock-in mouse models (PMID: 36232816). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Hemostasis Thrombosis GCEP on 08/26/2020. It was reevaluated on 04/02/2023 and 04/07/2025. As a result of this reevaluation, the classification did not change.
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: Hematologic
Rationale: Affected individuals can have excessive posttraumatic/postsurgical blood loss, as well as life-threatening bleeding episodes, and awareness may allow preventive measures and prompt treatment
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to P2RY12 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_022788.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 31 | 2 | 33 | |||
| missense | 3 | 82 | 4 | 1 | 90 | |
| nonsense | 2 | 2 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 2 | 5 | 8 | ||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 1 | 5 | 90 | 35 | 3 | 134 |
Highest pathogenic variant AF is 0.000047091016
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_073625.1 | 1 | MANE Select | |
| Ensembl | ENSP00000307259.4 | 1 | MANE Select | |
| RefSeq | NP_795345.1 | 1 | Standard | |
| Ensembl | ENSP00000625864.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Platelet activation - Homo sapiens (human)
- Clopidogrel Pathway, Pharmacokinetics
- Platelet Aggregation Inhibitor Pathway, Pharmacodynamics
- Ticlopidine Metabolism Pathway
- Clopidogrel Metabolism Pathway
Biological Process
- adenosine receptor signaling pathway
- substrate-dependent cell migration, cell extension
- G protein-coupled receptor signaling pathway
- adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway
- phospholipase C-activating G protein-coupled receptor signaling pathway
Molecular Function
- G protein-coupled adenosine receptor activity
- ADP receptor activity
- guanyl-nucleotide exchange factor activity
- G protein-coupled purinergic nucleotide receptor activity
Cellular Component
- mitochondrion
- plasma membrane
- caveola
- external side of plasma membrane
- basal plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000302632
- Coding exons
- 1
- Length
- 47433
- Individuals with no LoFs
- 125709
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 25
- Defined
- 125734
- p
- 0.0000994
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.863 | 152 | 185 | 0.821 | 0.00000973 | 2258 |
| Missense (PolyPhen) | 42 | 62.544 | 0.67153 | 781 | ||
| Synonymous | 0.181 | 70 | 72.0 | 0.973 | 0.00000396 | 683 |
| Loss of Function | 0.819 | 5 | 7.40 | 0.675 | 3.98e-7 | 98 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00038 | 0.00038 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000088 | 0.000088 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. Not activated by UDP and UTP. Required for normal platelet aggregation and blood coagulation. {ECO:0000269|PubMed:11104774, ECO:0000269|PubMed:11196645, ECO:0000269|PubMed:11502873, ECO:0000269|PubMed:12578987, ECO:0000269|PubMed:24670650, ECO:0000269|PubMed:24784220}.;
- Disease
- DISEASE: Bleeding disorder, platelet-type 8 (BDPLT8) [MIM:609821]: A condition characterized by mild to moderate mucocutaneous bleeding, and excessive bleeding after surgery or trauma. The defect is due to severe impairment of platelet response to ADP resulting in defective platelet aggregation. {ECO:0000269|PubMed:11196645, ECO:0000269|PubMed:12578987, ECO:0000269|PubMed:25428217}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.161
Intolerance Scores
- LoFtool
- 0.600
- RVIS EVS
- -0.18
- RVIS percentile EVS
- 40.16
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.187
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |