NUDT15*3 is assigned no function based on definitive evidence. In vitro studies using a bacterial expression system have found that NUDT15.3 enzymatic activity is significantly decreased or undetectable (26878724, 28659275, 33753169) and protein stability is decreased (29519865, 27530327, 33753169). In mammalian cells, NUDT15.3 protein expression is decreased (32094176, 38246006) and the protein was shown to be actively degraded by the proteasome (27530327). Additionally, NUDT15*1/*3 or NUDT15*3/*3 cell lines exhibit increased levels of DNA-TG and increased sensitivity to 6-MP compared to NUDT15*1/*1 cell lines (34636169). These data are supported by published structural analysis which indicates that the NUDT15*3 SNV, c.415C>T (p.R139C), disrupts the α-helix loop and the base of the substrate binding pocket, and may form a disulfide bond with residue 140, decreasing enzymatic activity (28088792). While the formation of a disulfide bond was not observed, the destabilizing effects of c.415C>T (p.R139C) were confirmed using an experimentally derived crystal structure of NUDT15.3 (33753169). Four out of nine variant effect predictors tested by CPIC staff predict that c.415C>T (p.R139C) impairs protein function. Mouse models of NUDT15*1/*3 or NUDT15*3/*3 are more susceptible to MP treatment and exhibit increased cytopenia and bone marrow failure compared to NUDT15*1/*1 mice (31645647). Additionally, HSCs derived from the bone marrow of NUDT15*3/*3 mice exhibit decreased viability and an upregulation of genes associated with DNA damage response and the cell cycle (37488179). The level of dose-normalized DNA-TG is increased in NUDT15*1/*3 or NUDT15*3/*3 patients (26878724, 34480209, 28445187, 33481917, 39688234) relative to NUDT15*1/*1 patients. Lastly, NUDT15*1/*3 or NUDT15*3/*3 patients tolerate significantly lower thiopurine doses compared to NUDT15*1/*1 patients (26878724, 33481917, 32598049, 28903549, 32308129, 29720126, 32873882, 36858569, 35156873, 32221476, 31507415, 27577869, 27416873, 26033531, 39688234) and experience an increased incidence of adverse reactions and/or therapy interruption (30728528, 37454061, 28903549, 36858569).