Introduction: Coronary Artery Disease (CAD) remains the leading cause of death despite effective therapies to lower serum cholesterol. To identify new mechanisms of disease for prevention and therapy, several recent genome-wide association studies (GWAS) have identified hundreds of loci with statistically significant association with CAD (5x10^-8). In a recent large meta-analysis of 181,522 cases and over 1 million controls subjects, the CARDIOGRAM consortium identified a locus with genome-wide significant association with CAD in the chromosome 7p14. Methods and Results: We functionally interrogated the chromosome 7p14 GWAS association with a combination of population genetics and in vitro experimental methods. Statistical fine-mapping identified a lead variant in the locus, rs2107732, with a posterior probability of association 63.5%. This variant has a significant association with CAD of P = 1.53 x 10^-8). The minor allele is present in 9.2% of subjects, reduced risk of CAD (OR=0.92), and encodes a valine to isoleucine substitution in CCM2 at amino acid position 74 (V74I). To understand the importance of CCM2 and the coding mutation V74I in CAD, we first knocked-down CCM2 in immortalized human aortic endothelial cells (teloHAECs). KLF2, a critical athero-protective gene, was upregulated upon CCM2 knockdown. However, overexpressing wildtype CCM2 decreased the level of KLF2, and overexpressing CCM2 with the V74I mutation downregulated KLF2 to a comparable level. To circumvent the potential interference from the endogenous wildtype CCM2, we used CRISPR-Cas9-mediated homology-directed repair in teloHAECs and generated multiple clones carrying homozygous CCM2 V74I mutation. These clones will serve as useful tools to understand the mechanism by which CCM2 V74I mutation decreases the risk of CAD. Conclusions: We identified a missense mutation in CCM2 which is associated with a decreased risk of coronary artery disease. Functional analysis of CCM2 in arterial endothelial cells suggests that the protective effect is through upregulation of KLF2 expression.