P2RY12

Chr 3AR

purinergic receptor P2Y12

Also known as: ADPG-R, BDPLT8, HORK3, P2T(AC), P2Y(12)R, P2Y(AC), P2Y(ADP), P2Y(cyc)

NCBI Gene: 64805 ENSG00000169313 UniProt: Q9H244 OMIM: 600515

This gene encodes a G-protein coupled receptor for ADP and ATP that inhibits adenylyl cyclase and is required for normal platelet aggregation and blood coagulation. Mutations cause bleeding disorder, platelet-type 8, an autosomal recessive condition affecting hemostasis. The gene is not highly constrained against loss-of-function variants (pLI = 0.002, LOEUF = 1.41), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.411 OMIM phenotype

Clinical Summary— P2RY12

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Gene-Disease Validity (ClinGen)

platelet-type bleeding disorder 8 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

21 unique Pathogenic / Likely Pathogenic· 233 VUS of 348 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.41LOEUF

pLI 0.002

Z-score 0.82

OE 0.68 (0.35–1.41)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.86Z-score

OE missense 0.82 (0.72–0.94)

152 obs / 185.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.68 (0.35–1.41)

0≤0.351.4

Missense OE?0.82 (0.72–0.94)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 5 / 7.4Missense obs/exp: 152 / 185.0Syn Z: 0.18

This gene — mechanism propensity

0.78top 25%

GOF

0.80top 10%

LOF

0.2288th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

348 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic15

VUS233

Likely Benign64

Benign12

Conflicting7

Pathogenic

Likely Pathogenic

233

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	1	0	0	6
Likely Pathogenic	12	3	0	0	15
VUS	5	223	5	0	233
Likely Benign	0	16	5	43	64
Benign	0	2	4	6	12
Conflicting	—				7
Total	22	245	14	49	337

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

19 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap P2RY12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →