Recently, a modest-sized population-based study of exonic variants facilitated the identification of the causal gene, TM6SF2, in a gene-rich locus on 19p1 previously associated with cholesterol levels in blood. The study also provided compelling functional validation of the locus and evidence at the population level that interference with the function of this gene may substantially reduce the risk of coronary artery disease. The study highlights the potential utility of large-scale studies of coding variants but also hints toward the need of much larger studies to provide insight at other loci. Conducting such studies in parallel with association studies of variation in well-annotated regulatory regions is likely to ultimately yield the highest returns.