TPMT*21 is assigned no function based on moderate evidence. Erythrocytes from individuals genotyped TPMT*1/*21 exhibited intermediate activity (18602085, 16917910, 23252716). Additionally, a patient genotyped TPMT*1/*21 was prescribed 41 mg/m2 thioguanine and exhibited a plasma TGN concentration of 4060 pmol, which is above the therapeutic range (23252716). Erythrocytes from an individual genotyped TPMT*3A/*21 had undetectable enzymatic activity (33118454). An in vitro study using a mammalian cell expression system found that TPMT.21 enzymatic activity was undetectable (18708949). An additional in vitro study using a yeast expression system found that TPMT.21 enzymatic activity is decreased by 75% compared to TPMT.1 and molecular modeling suggests that TPMT.21 alters the co-factor binding site (18602085). Seven out of ten variant effect predictors tested by CPIC staff predict that the TPMT*21-defining SNV, c.205C>G (p.L69V), impairs protein function.