the Input Level in the Setup menu sets a signal-to-noise ratio. set this for your loudest guitar, and leave it there for the other guitars. this does not affect level/gain into Presets/Layout unless there is a major difference, like one guitar would be set at 100% and the other at 5%. in majority of cases, setting for your loudest guitar works well for all guitars you use.
if by Input Gain you mean a block somewhere, this is an actual Level/Signal adjustment where it will get noticeably louder or quieter. you shouldn't need to adjust this at all in most cases.
the Amp block has the most affect on Level/Signal, because different Input Drive, Master Volume and other settings really change the perceived volume. that's why it's the best place to adjust your overall level. it's the source of level, so adjust it at the source.
the main issue with only using the Out block is that say you have an Amp block set to -30dB or something, and it's really quiet. the Out block could only boost 20dB more, and if that's not enough to get the level you need, you have to adjust something else anyway. similarly, if you have a very loud Amp due to Drive and Master Volume settings, and you turn the Out block down but it can't get quiet enough, you'd have to adjust somewhere else too.
so it's best practice to adjust the Level at the Amp block since it's responsible for very big changes in perceived volume. once your Level is balanced in general with those Drive settings, use Scene Volumes, or the Out block to adjust if needed. but it's best to make the big initial balance changes from the source.
