GPR41 and GPR42 are two closely related genes that are part of a cluster of four adjacent G protein-coupled receptors (GPCRs) (GPR40, 41, 42, and 43) localized on human chromosome 19. There are only six nucleotide and amino acid differences between GPR41 and GPR42. High sequence homology between these two genes suggests that they are the result of a recent duplication event. Mutagenesis studies have previously shown that amino acid 174 is important for functional signaling since conversion of R174 (found in GPR41) to W174 (found in GPR42) silences the response to short chain fatty acids, raising the possibility that GPR42 might be an inactive pseudogene. In the present study, we present evidence showing that the six amino acid differences, including that R/W174 are polymorphisms rather than gene-specific differences between GPR41 and GPR42. Most importantly, of the 202 GPR42 alleles that were genotyped, 123 (61%) had arginine at amino acid 174, suggesting that GPR42 could potentially be a functional gene in a significant fraction of the human population and should therefore not be categorically characterized as an inactive pseudogene. In addition, a second copy of GPR40 was found to localize between GPR41 and GPR42 genes in human and chimp, suggesting that the duplication event that generated GPR42 in human and chimp might have involved a 12.5 kb DNA fragment that also contains GPR40. This second copy of the GPR40 gene is a pseudogene since it has diverged extensively from GPR40 and does not contain an open reading frame.