jats:titleAbstract</jats:title>jats:pMany 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 jats:italicPROCR</jats:italic> locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify jats:italicPROCR</jats:italic>-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 jats:italicPROCR</jats:italic>-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 jats:italicPROCR</jats:italic>-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links jats:italicPROCR</jats:italic>-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.</jats:p>