NUDT15*4 is assigned no function based on strong evidence. Clinical studies have found that NUDT15*1/*4 or NUDT15*2/*4 patients are started on lower doses of thiopurines and exhibit a greater incidence of leukopenia and therapy interruption compared to NUDT15*1/*1 patients (28903549, 36858569). Retrospective analysis found that NUDT15*1/*4 patients tolerated lower thiopurine doses (26878724, 39688234) and exhibited increased levels of dose-normalized DNA-TG in leukocytes compared to NUDT15*1/*1, *1/*2, and *1/*3 patients (39688234). In vitro evidence shows that NUDT15.4 exhibits decreased enzymatic activity (26878724, 33753169), decreased protein expression (32094176) and decreased thermostability (26878724, 28088792, 33753169) compared to NUDT15.1. Published structural modeling indicates that the functional SNV (c.416G>A (p.R139H)) disrupts the α-helix loop and the base of the substrate binding pocket (28088792). These structural destabilizing effects were confirmed using an experimentally derived crystal structure of NUDT15.4 (33753169). Five out of nine variant effect predictors tested by CPIC staff predict that the NUDT15*4-defining SNV, c.416G>A (p.R139H), impairs protein function .