variants (60.3%) and due to the distinctively divergent but overlapping trends in the distributions of bioactivities between WT and variants (Supplementary Figure ). These results highlight the importance of variant awareness in bioactivity modelling but do not provide a solid basis for general recommendations on the variant-aware strategy that should be used. Next, the capacity of models to predict the bioactivity of compounds on unseen variants was investigated. To this end, Leave-One-Variant-Out (LOVO) cross-validation was carried out.