The first observation from review of the VEBD was that bioactivity data points were not homogeneously distributed across protein families. Proteins were assigned to their corresponding protein families using the levels L1-L5 in the protein family classification table in ChEMBL. Out of the 455,839 bioactivity data points in the VEBD, more than half were in enzymes (266,328), followed by membrane receptors (96,037) and then the remaining protein families (Figure , Supplementary Table ). The percentage of variant-tested bioactivity data with respect to the total amount of bioactivity datahereby referred to as variant bioactivity percentagewas highest for secreted proteins (10.8%) followed by enzymes (7.8%), but in both cases, it was in the same order of magnitude as the variant bioactivity percentage for the whole dataset (5.5%). Of note, the secreted proteins family included only one protein while the enzymes family included 195. Compared to the highest classification level of protein families, the variant load drastically differed between protein subfamilies. For example, the variant bioactivity percentage across subfamilies of the kinase enzyme family ranged from 0.1% for the CMGC protein kinase group to 35% for the TKL protein kinase group (Figure , Supplementary Table ). Similar trends were observed while focusing only on ChEMBL-exclusive data and exploring the differences between the original and the current variant annotation pipelines. The highest amount of bioactivity data points with potential novel variant annotations corresponded to enzymatic targets (3,631), followed by membrane receptors (218). However, at the highest protein classification level, the percentage of potentially novel annotated bioactivity data to the totality of the variant-annotated data significantly differed across protein families, ranging from 0% in secreted proteins to 17.5% in enzymes (Figure , Supplementary Table ). Again, this effect was exacerbated across kinase subfamilies. Here, in four subfamilies (i.e. atypical, STE, CK1, and CAMK protein kinase groups) the totality of the variant bioactivity data had previously been annotated in ChEMBL, resulting in a novel annotated variant bioactivity percentage of 0%, while in the AGC protein kinase group, 89.7% of the variant data was introduced by the current variant annotation pipeline (Figure , Supplementary Table ).