NUDT15*5 is assigned decreased function based on moderate evidence. Patients genotyped NUDT15*1/*5 or NUDT15*3/*5 exhibited increased dose-normalized levels of DNA-TG compared to patients genotyped NUDT15*1/*1 (33481917). Intermediate metabolizers, including those genotyped NUDT15*1/*5, have been shown to tolerate lower thiopurine doses (33481917, 32221476, 36873097, 33504140) and exhibit an increased risk of neutropenia (36873097). One patient genotyped NUDT15*3/*5 exhibited similar thiopurine intolerance to a patient genotyped NUDT15*3/*3 (26878724). In vitro studies using a bacterial expression system found that NUDT15.5 exhibits decreased enzymatic activity and decreased protein stability compared to NUDT15.1 (26878724, 33753169). However, published in silico analysis indicates that the NUDT15*5-defining SNV, c.52G>A (p.V18I) has minimal effect on protein structure and NUDT15.5 exhibits similar thermostability as NUDT15.1 (28088792). Despite these predictions, an experimentally derived crystal structure of NUDT15.5 found that c.52G>A (p.V18I) destabilizes the conserved NUDIX motif (33753169). Five out of nine variant effect predictors tested by CPIC staff predict that c.52G>A (p.V18I) impairs protein function. An additional in vitro study found that the NUDT15.5 protein is expressed at similar levels to NUDT15.1 and does not affect 6-MP sensitivity in HEK293 cells (32094176).