CYP2B6*6 (c.516G>T, p.Q172H/splice defect and c.785A>G, p.K262R) - Decreased function: CYP2B6*6 is assigned decreased function based on in vivo (homozygous and heterozygous patients) and in vitro studies. Significantly lower protein expression and activity was found in human liver microsomes, and increased plasma exposure of CYP2B6 substrates was found in healthy volunteers and patients. In a panel of 87 human liver microsome samples, the CYP2B6*6 allele was associated with significantly decreased protein expression and activity, measured by bupropion 4-hydroxylation and efavirenz 8-hydroxylation (17559344). The mechanism was predominantly aberrant splicing caused by c.516G>T (but not c.785A>G) leading to reduced content of functional mRNA, protein, and activity (14551287, 18171905, 24260284). Multiple in vitro studies using human liver microsomes (17559344, 22232427, (23550066) and cDNA expression systems (21659470, 32238417, 35538637) found that CYP2B6*6 has decreased enzyme activity and metabolism of efavirenz, bupropion, methadone and ketamine. Although two other in vitro studies using cDNA expression systems found increased activity (12642465, 30201214), the experts did not find these results convincing. This discrepancy is probably due to differences in the in vitro expression systems and substrates used. Multiple studies evaluating efavirenz plasma concentrations among patients with HIV found that CYP2B6*6 carriers had higher efavirenz concentrations compared to the *1 reference (e.g., 15194512, 17235330, 27799204). A study evaluating efavirenz content in hair samples among HIV patients taking efavirenz for more than three months similarly found that CYP2B6*6 was associated with greater long term efavirenz exposure (26655325). Other studies using c.516G>T as a tagSNP for CYP2B6*6 (15622315) showed that G/T and T/T genotypes (compared to G/G) were associated with significantly higher efavirenz plasma exposure during HIV therapy. Several studies found that plasma exposure of the active bupropion metabolite hydroxybupropion was less in CYP2B6*6 carriers than in the *1 reference, although bupropion concentration and clearance were unchanged (23344581, 25565674, 29756345, 34752647). Multiple clinical studies of methadone, evaluating metabolism and/or clearance, have shown that methadone plasma exposure (S- more than R-) is greater and/or metabolism and clearance is less in CYP2B6*6 carriers compared to the *1 reference (16338275, 17178267, 17329992, 25456329, 26389554, 28723731, 32302325 ). Therefore, consensus among experts was decreased function based on strong evidence.