Gene-level association analysis of rare variants (MAF < 0.5%) identified 4 genes at exome-wide significance: MC4R, PAM, SLC30A8 and UBE2NL. Of note, the association of SLC30A8 with T2D was driven by 90 missense variants, where the reduced protein activity was linked to decreased T2D risk. The gene discussed is MC4R; the disease is type 2 diabetes mellitus.