Only direct single-atom substitutions (i.e. n=0) result exclusively in perturbations with SEM ∆G solvated < 0.5 kcal•mol -1 . Although this relation with the number of perturbed heavy atoms reflects favourably on state-of-the-art MCSS rule-based methods, the noisy nature of this relation suggests that there is scope for more accurate methods to model statistical fluctuations of RBFEs.