A rare variant of a gene called SVEP1 has been found to play an important role in atherosclerosis development. Previous studies have shown that SVEP1 is associated with a high risk of coronary disease in humans, independent of plasma lipids levels. However, it has not been clear whether this gene is involved with the development of atherosclerosis. In this new study, researchers show that a rare genetic variant of SVEP1, called p.D2702G, promotes atherosclerosis in both humans and mice. This variant is expressed by vascular smooth muscle cells within the atherosclerotic plaque. This interaction eventually leads to proliferation and dysregulation of key differentiation pathways, causing inflammation and promoting atherosclerosis. The findings may help design targeted therapies that inhibit this SVEP1 variant and grant protection from atherosclerosis.