Allele Nucleotide or Structural Change Effect on Total CYP2A6 Activity Reference CYP2A6*1A Wild type Normal [50] CYP2A6*1x2 Gene duplication (increased copy number)1 Increased [40,58] CYP2A6*1B Gene conversion in 3’UTR (increased mRNA stability)2 Increased [59,61, 206,207] CYP2A6*1H SNP in 5’ flanking region decreases promoter activity (expression) Decreased [57] CYP2A6*2 SNP in exon 3 (produces L160H mutated protein) No activity [50,51,208] CYP2A6*3 Gene conversions in exons 3, 6, 8 (CYP2A6/CYP2A7 hybrid)(very rare) No activity [209] CYP2A6*4 Gene deletions resulting from unequal crossover events between CYP2A6 & CYP2A73 No activity [60,210-212,214] CYP2A6*5 SNP in exon 9 (produces G479V mutated protein with reduced enzyme levels) & gene conversion in 3’-UTR4 Decreased [60] CYP2A6*6 SNP in exon 3 (produces R128Q mutated protein with decreased intrinsic activity) Decreased [52] CYP2A6*7 SNP in exon 9 (produces I471T mutated protein with decreased intrinsic activity) Decreased [53,215] CYP2A6*8 SNP in exon 9 produces R485 mutated protein   [216] CYP2A6*9 SNP in TATA box5 (decreases promoter activity) Decreased [56,217-219] CYP2A6*10 Two SNPs in exon 9 (produces I471T & R486L mutated protein) Decreased [215,220] CYP2A6*11 SNP in exon 5 (produces S224P mutated protein) Decreased [221] CYP2A6*12 Unequal crossover in intron 2 between CYP2A6 & CYP2A7 (hybrid allele: 5’-flanking region and exons 1-2 of CYP2A7; exons 3-9 and 3’UTR of CYP2A6) (produces protein with 10 amino acid substitution with decreased intrinsic activity) Decreased [222,223] CYP2A6*17 SNPs in exons 1, 3, 7, and 8 and in introns 1, 6, 7,and 8 SNP in exon 7 produces V365M mutated protein Decreased [43,45,54] CYP2A6*18 SNP in exon 8 produces Y392F mutated protein6 Decreased [55,216] CYP2A6*19 SNPs in exon 8 and 9 produce Y392F and I471T mutated protein Decreased [55,216] CYP2A6*20 A 2-nucleotide deletion in exon 4 produces a frame shift at codon 196; results in premature stop codon at exon 220 in exon 5 (truncated protein) No activity [43,224] CYP2A6*21 SNP in exon 9 produces K476R mutated protein Decreased [43] CYP2A6*22 SNP in exon 3 produces D158E and L160I mutated protein Decreased [225] CYP2A6*23 SNP in exon 4 produces R203C mutated protein Decreased [43,45] CYP2A6*24 SNPs in exons 2 & 9 produce V110L, N438Y mutated protein; also contains the same 58bp CYP2A7 3’-UTR seen in CYP2A6*1B allele7 Decreased [43] CYP2A6*25 SNP in exon 3 produced F118L mutated protein Decreased [43] CYP2A6*26 SNPs in exon 3 produce F118L, R128L, & S131A mutated protein Decreased [43] CYP2A6*27 SNPs in exon 3 & 4 produce F118L mutated protein with frameshift at codon 203 (R203FS) Decreased [43] CYP2A6*28 SNPs in exon 8 produce a N418D & E419D mutated protein; also contains the same 58bp CYP2A7 3’-UTR seen in CYP2A6*1B allele8 Decreased [43] CYP2A6*35 SNP in exon 9 produces N438Y mutated protein9 Decreased [216,226]

Table 1: CYP2A6 polymorphisms with proposed effects on nicotine metabolism. (Note: 1Two variants of CYP2A6*1x2 have been identified, CYP2A6*1x2A & CYP2A6*1x2B. The two forms are both the product of unequal crossover between CYP2A6 & CYP2A, resulting in a gene