Here we analyzed 70 publicly available KRAS SII-P binder co-crystal structures related to Thr58 associated conserved water and found that it is present in most of the KRAS SII-P binder cocrystal structures (apart from a small subset of the G12C inhibitors and the first reported G12R inhibitor). This conserved water likely plays an important role on the switch-II functionality, as it connects b1-sheet (Gly10) to the highly flexible switch-II (Thr58), and it is observed with numerous of KRAS structures, including active signaling state structures (KRAS -effector protein complexes) (Table ). KRAS T58I mutations have been found in Noonan syndrome and it also appears rarely in different cancers (14 patients in GENIE Cohort v.12.0-public). The biochemical consequences of T58I are still unclear but most likely KRAS activating. Overall, this highlights the importance of the key Thr58 residue in KRAS functionality.