Severe obesity is a complex chronic metabolic condition with a body mass index over 40 and can be caused, for example, by dysregulated G protein–coupled receptors (GPCRs) signaling. The orphan GPCR GPR61 had been linked to the regulation of metabolism and, here, we identify 34 mutations in the GPR61 gene which are present with much higher frequency in severe obesity samples from the UK10K obesity screen compared to the normal population. Furthermore, the cumulative sum of GPR61 mutations was found to be higher compared to the highly mutated and well-established target, melanocortin 4 receptor. Some GPR61 mutations presented an impact on ligand-independent GPR61-induced cAMP production. Specifically, R236C5.66 compromised Gs protein activation and altered the pattern of cellular expression. Our data warrant further studies to assess the role of this orphan GPCR in metabolism in greater detail. Significance Statement: This study identified missense mutations, including previously unknown variants, of the GPR61 gene in severely obese patients. This occurrence was higher than for the well-established obesity target melanocortin 4 receptor. In the in vitro assays, 3 mutations of GPR61, in particular R236C5.66, were loss of function because they reduced the constitutive activity of the receptor. The data support the notion that GPR61 can act as a promising target in obesity and its functions should be explored in future studies.