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Recent machine learning (ML) systems have used hierarchical biological knowledge to associate genetic mutations with phenotypic outcomes, yielding substantial predictive power and mechanistic insight. Here, we use an ontology-guided ML system to map single nucleotide variants (SNVs) focusing on 6 classic phenotypic traits in natural yeast populations. The 29 identified loci are largely novel and account for ~17% of the phenotypic variance, versus &lt;3% for standard genetic analysis. Representative results show that sensitivity to hydroxyurea is linked to SNVs in two alternative purine biosynthesis pathways, and that sensitivity to copper arises through failure to detoxify reactive oxygen species in fatty acid metabolism. 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