“…Both of these expected scenarios tempt investigators to extrapolate the outcome from one variant (or a few) to the overall role of the position being substituted (neutral or toggle). However, this inference is not appropriate for a third class of protein positions: We observed this class in an experimental study of select nonconserved positions in LacI/GalR homologs (Meinhardt & Swint‐Kruse, ; Meinhardt et al., ; Tungtur, Egan, & Swint‐Kruse, ; Tungtur, Meinhardt, & Swint‐Kruse, ; Tungtur, Parente, & Swint‐Kruse, ). Many substitutions did alter protein function which indicated that, despite their nonconservation, these positions were important (and thus, not neutral).…”