AbstractObjective: To identify and functionally characterize single‐nucleotide polymorphisms (SNPs) in melanin‐concentrating hormone (MCH)‐R1 and ‐R2.Research Methods and Procedures: The entire coding regions and intron/exon splice junction regions ofMCH‐R1andMCH‐R2were sequenced from anonymous white (n= 45) and African‐American (n= 46) individuals. DNA was analyzed, and SNPs were identified using Phred, Phrap, and Consed software. DNA constructs containingMCH‐R1andMCH‐R2SNPs were generated and expressed in CHO cells. The effect of the SNPs inMCH‐R1andMCH‐R2were assessed in receptor binding assays and functional assays measuring changes in intracellular cAMP and Ca2+levels.Results: We identified 12 SNPs in theMCH‐R1gene. Two of these SNPs are in coding regions, and one produces an arginine‐for‐glycine substitution at residue 34 in the MCH‐R1 sequence. This SNP is present at a minor allele frequency of 15% in the African‐American population tested in this study. We identified eight SNPs in theMCH‐R2gene. Four of these SNPs are in coding regions, and two produce amino acid substitutions. Lysine substitutes for arginine at residue 63 of the African‐American population, and glutamine substitutes for arginine at residue 152 in whites (minor allele frequency of 2% for both SNPs). No changes in receptor binding or functional signaling were observed with the SNP mutations inMCH‐R1orMCH‐R2.Discussion: These data indicate that potential therapeutics designed to act at the MCH receptor are unlikely to have altered effects in subpopulations that express variant forms of MCH‐R1 or MCH‐R2.