We characterized 48 rare MC4R variants (minor allele frequency [MAF], <1%) associated with severe obesity in clinically ascertained cohorts (Farooqi et al., 2003; Hinney et al., 2006; Stutzmann et al., 2008) and two prevalent MC4R variants (MAF, 1%–2%; V103I and I251L) associated with protection from obesity in large population-derived studies (Lotta et al., 2019; Stutzmann et al., 2007; Wang et al., 2010; Young et al., 2007; Figure 1A; Table S1). The gene discussed is MC4R; the disease is obesity disorder.