Description:A goal of biology is to predict the phenotypes of individuals, such as side effects to drugs, from their genotypes. Genetic variants that cause disease can change an individual’s total metabolite profile, or metabolome. Understanding the function of these genetic variants may help predict novel phenotypes. We used an unbiased method in yeast to show that genetic differences in two genes change the levels of several urea cycle metabolites. Leveraging knowledge of the urea cycle, we then predicted and validated the sensitivity of yeast strains to a particular drug. The interpretability of our results demonstrates the promise of using genetic variants underlying differences in the metabolome to predict novel phenotypes from genotype.