In this study, we identified pLOF variants that protect against obesity (GPR151), asthma (GSDMB, IL33), autoimmune disorders (IFIH1), and coronary artery disease (PDE3B), prioritizing genes and pathways for which pharmacologic attempts to mimic these protective mutations might ameliorate disease. Here, GPR151 is linked to obesity due to melanocortin 4 receptor deficiency.