Significance: Pharmacogenetics is a prototype of genomics-guided precision medicine. While there is a rapid expansion of novel pharmacogenetic variants discovered by genome sequencing, the lack of variant interpretation in a scalable fashion is a formidable barrier in this field.NUDT15polymorphism is a major genetic cause for hematopoietic toxicity during thiopurine therapy. Motivated by the need to understandNUDT15variant effects for clinical actions, we developed a massively parallel assay to preemptively characterize 91.8% of all possible missense variants inNUDT15. Our function-based variant classification accurately predicted thiopurine toxicity risk alleles in patients. These results vastly improved the ability to implement genotype-guided thiopurine therapy and illustrated the value and potential of a high-throughput variant effect screen in general.