Based on the interaction of MRAP2 with MC4R (155541), an energy homeostasis protein implicated in obesity, and the phenotype of Mrap2-null mice, Asai et al. (2013) investigated whether alterations in MRAP2 are associated with human obesity. They sequenced ... Based on the interaction of MRAP2 with MC4R (155541), an energy homeostasis protein implicated in obesity, and the phenotype of Mrap2-null mice, Asai et al. (2013) investigated whether alterations in MRAP2 are associated with human obesity. They sequenced the coding and intron-exon boundaries of MRAP2 in obese and control individuals from the Genetics of Obesity study cohort (Farooqi and O'Rahilly, 2006) and the Swedish obese children's cohort (Johansson et al., 2009). Asai et al. (2013) identified 4 rare heterozygous variants in unrelated nonsyndromic severely obese individuals that were absent from cohort-specific controls and 1000 Genomes, with all but 1 variant in the C-terminal region of the protein. In 3 of these subjects, no pathogenic variants were found in the coding region or intron-exon boundaries of all nonsyndromic human obesity genes known to that time. Only one of the variants, a nonsense mutation (615410.0001), was clearly disruptive, and overall, few rare variants were found in the obese cohorts, indicating that if MRAP2 mutations contribute to severe human obesity, they do so rarely.