Increasing low-density lipoprotein receptor (LDLR) re-cycling by blocking the proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces LDL cholesterol and subsequently cardiovascular morbiditiy and mortality. However, other proteins are also involved in LDLR cycling and here the authors demonstrate a role for CCDC93. CCDC93 p.Pro228Leu was dose-dependently associated with lower LDL cholesterol and lower risk of myocardial infarction and cardiovascular mortality. The variant of CCDC93 was shown to increase CCDC93 protein stability, and overexpression of human CCDC93 decreased plasma LDL cholesterol in mice. Conversely, CCDC93 ablation reduces LDL uptake as a result of reduced LDLR levels at the cell membrane. Thus, a new target protein involved in cholesterol metabolism affecting cardiovascular morbidity and mortality have been identified.