CYP2B6*4 (c.785A>G, p.K262R) - Increased function: CYB2B6*4 is assigned increased function based on in vivo (heterozygous patients only) and in vitro studies. In clinical studies, CYP2B6*4 heterozygotes had significantly increased metabolism of several substrates such as bupropion (14515060, 29637923), nicotine (17015050) and efavirenz (17235330). Numerically higher methadone clearance was observed in CYP2B6*4 carriers, albeit samples sizes were small (26389554, 35538637). Although two studies did not find increased efavirenz clearance compared to the *1 reference (23399569, 23254426), the experts did not find these results convincing due to the small sample size. Multiple in vitro studies using cDNA expression systems showed that CYP2B6*4 has increased activity compared to the *1 reference towards efavirenz, methadone, bupropion nicotine, artemether and selegiline, (12642465, 21746968, 21821736, 31324697, 32238417). One in vitro study using cDNA expression system showed no difference in activity using bupropion as a probe (21659470), but the experts did not find this evidence convincing. Some studies found CYP2B6*4 had less activity compared to the *1 reference towards ketamine, nicotine, cyclophosphamide and ifosphamide (21821736, 21976622, 25934575, 30085944, 30906561). This discrepancy is probably due to differences in the in vitro expression systems and substrates used. Therefore, consensus among experts was increased function based on moderate evidence, but effects may be substrate-dependent.