Many individual genetic risk loci have been associated with multiple common human diseases. However, the
molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the
molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk
but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant
at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro
experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through
endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte–
endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-
thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD
through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a
framework to reveal the mechanisms underlying similar cross-phenotype associations.