First of all: the largest contributor of 'stuff' to most people's disk storage is User documents.
None of these have to be in the user folder, and there is no problem opening and saving from an external drive (and there never has been). If space is a concern, then I would simply store all your documents on an external.
Don't forget that you'll need another external drive for your backup disk.
Most Applications can also be launched from any location. However, some applications install a variety of support files, which need to be in
/Library/Application Support or other Library subfolder, (or the user's equivalent Library folder).
Apps also have working caches, preferences, and other files which are saved in the User's Library.
I would recommend leaving applications in their default location. You are unlikely to fill a 256 GB drive just with System and Apps.
Other files, like Photos.app's library, "iTunes" archive, Garageband samples, etc are normally stored on the system disk, but can be configured to other locations.
For a laptop, I would always recommend getting the largest internal storage you can afford (and then maybe some more!); but for an iMac or Mini, there's no inconvenience from an attached device.