CYP2C9*8 is assigned decreased function based on definitive evidence in heterozygous patients and in vitro studies. Ten CYP2C9*1/*8 genotype patients on a stable warfarin dose had 28% lower S-warfarin clearance compared to wildtype patients which correlated with the in vitro kinetic study demonstrating the CYP2C9*8 protein had 30% reduced warfarin clearance compared to wildtype (22378156). The CYP2C9*8 allele was associated with decreased phenytoin metabolism in 19 subjects (CYP2C9*1/*8, CYP2C9*8/*9, CYP2C9*8/*11, or CYP2C9*5/*8) compared to wildtype subjects based on urinary excretion of a phenytoin metabolite after a single 300mg dose (16220110). Four CYP2C9*1/*8 subjects had decreased diclofenac metabolism compared to wildtype subjects based on the urinary metabolite ratio after a single 50mg dose (23959274). One in vitro study showed CYP2C9*8 had decreased mRNA expression compared to wildtype, resulting in decreased function and metabolism of substrates (23376925). Decreased metabolism of multiple substrates compared to wildtype was demonstrated in a series of in vitro studies (23752738, 27199745, 23844998, 24118918, 25142737, 25144335, 25476996, 25832633, 25884291, 25924705, 27163851, 25951663, 24077631). Although an in vitro study showed similar diclofenac metabolism compared to wildtype (22378156), the experts did not find this conflicting because four CYP2C9*1/*8 subjects exhibited decreased diclofenac metabolism as previously described (23959274). Additionally, the experts did not deem two in vitro studies where CYP2C9*8 demonstrated similar to increased enzyme activity compared to wildtype (28758225, 15284535) as conflicting evidence because both studies used the same system, and it could not be ruled out that these results which differed from the majority of in vitro studies were due to the specific system. Although six CYP2C9*1/*8 subjects had similar acenocoumarol metabolite plasma concentrations compared to wildtype subjects 8 and 24 hours after a single 8mg dose (21811894), the experts did not deem this result as conflicting evidence based on the small sample size. Similarly, two CYP2C9 *1/*8 subjects had a similar urinary losartan-metabolite ratio compared to wildtype after a single 25mg dose and the experts did not deem this result as convincing conflicting evidence based on the small sample size (15289788). Therefore, consensus among experts was decreased function with an activity value of 0.5 based on definitive evidence.