I've seen a few project examples where the (full size) CP had different layouts for P1 and P2 (usually the infamous "mirror" or "symmetrical" layout where the joystick is on the opposite side of the buttons for P2). That's usually the first thing that sticks out and everything else just seems inconsequential at that point.
That being said, there are maybe three legitimate times when multiple players do not match:
First: Bartops are typically most comfortable as one player affairs and the second stick is more for Robotron, etc. where being able to play a two-player game is a "bonus" and not some "advertised feature".
Second: quite a few real four player games have the buttons it a slightly different position from the joystick for spacing reasons. These are simple beat-em-up and the buttons could be almost anywhere and be effective anyhow.
And finally: if you're the only one going to be using the machine with regularity, you can conveniently have two different sets of layouts for different games (e.g. SF on the left and MK on the right; straight on left, curved on right) without multiple panels.