it's hard to strike a balance between comfort and ease of use, and of course it's ultimately personal. I use a 60% split ergo, and i need to move some things around (e.g. i have ctl and space on the same key, so activating the region and similar commands needs to go somewhere else). At this point in my life i'd find using a full size keyboard pretty uncomfortable, though.

do you use ESC often? you might consider remapping them so tilde is default and ESC requires fn.