Three common haplotypes of the human catechol-O-methyltransferase (COMT) gene are associated with experimental pain sensitivity. Based on subjects' pain responsiveness, haplotypes were designated as low (LPS), average (APS), or high (HPS) pain sensitive; APS and HPS haplotypes exhibit lower COMT enzymatic activity. Minor frequency SNPs naturally occur within the APS and HPS haplotypes, but their functional impact is unknown. We hypothesized that these minor SNPs, one occurring in the APS construct (G/A, rs769224) and three in the HPS construct (G/T, rs6267; G/A, rs740602; C/T, rs8192488), may compensate for the observed reductions in enzymatic activity. Testing was carried out via transient transfection of rat adrenal (PC-12) cells with each of the four constructs. No difference exists between the haplotype mutants and their respective parent haplotype for RNA abundance, protein expression, or enzymatic activity (P > 0.05). Additionally, the minor allele of SNP re6267 is a likely marker of the HPS haplotype.