Apart from the 8,455 assay-target pairs with extracted substitutions, 1,600 pairs were found to be annotated only in ChEMBL and not identified by the current variant annotation pipeline. These ChEMBL-only annotated pairs were further evaluated in light of the underlying reasons that led to their exclusion from the current variant annotation pipeline (Supplementary Table , Supplementary Figure ). ChEMBL substitutions missed by the regular expression, such as those with unconventional definitions, were incorporated into this analysis unless their initial annotation was "undefined" or a deletion. Extracted substitutions failing validation against the WT sequence were categorised into three groups: 1) If the extracted substitutions matched those in ChEMBL in all aspects except the residue number, the original substitutions were considered a sequence number shift exception and included. 2) If the extracted substitutions fully matched the original ChEMBL annotation but were not valid according to the WT sequence, they were either a) excluded (i.e. if the associated target was a protein family) or b) classified as ambiguous due to a sequence mismatch. 3) Finally, if the extracted substitutions did not align with the original annotation, they were deemed ambiguous due to substitution mismatch or omission and are under review. This analysis led to the classification of ChEMBL-only variants into true negatives (686 misclassified ChEMBL annotations), false negatives (798 ChEMBL expert annotations), and ambiguous (416 ChEMBL-only annotations). True negatives were excluded from the final dataset, while false negatives were rescued from ChEMBL and included. Pairs in the ambiguous group were flagged as undefined variants and included in the final dataset. After the annotation feedback loop, 9,229 assaytarget pairs (774 additional assays) were annotated with variants. These were annotated with a variant target identifier as done in the Papyrus dataset by adding the amino acid substitutions as a suffix to the UniProt accession code of the protein. Similarly, bioactivity data points tested on WT proteins were identified by the suffix "WT" after the accession code. Note that the final number of annotated pairs relies on the feedback loop, which is currently under revision; thus, the ultimate count is subject to change in an updated version.