AGCEEP is designed to be more historical. Loads more events to guide your country. Harder and more consequences for going around and eating up half of Europe.
Interregnum is overwhelmingly ahistorical. Features all of the nations that could have been but weren't. Designed to have a starting balance of power, for multiplayer play.
Europa Portugalis, I believe, has improved AI making it extra hard so you aren't completely dominating by 1550. Haven't really tried it yet, so I probably can't explain too much more than that.
Others like 476, Dark Ages, etc. set up a game in an alternate time period.