With all the VI references abounding on Azys Lla, but in an effort to be original, I'm somewhat hoping Varis inadvertently absorbs the power of the Warring Triad and goes crazy (either from the power destabilizing his mind or because he's become a container for the same things his people despise), and van Hydrus turns on him a la General Leo and allies with us. Either we fail to stop him from using Light of Judgment or lessen the damage, but either way we fail and the world is devastated.
Mostly because they've said 4.0 won't require 2.0 - 3.x completion to jump into it, and while I hate for a Calamity to be used as another reset button I can't currently think of another way to implement this. I can also easily picture a truly desperate battle against a power-drunk/mad Varis with the Black Mages mix of Dancing Mad and, even though I barely played VI much, WANT IT SO BAD BECAUSE IT WOULD BE SO DAMN EPIC. Have us fail in a visceral way, not the "Dalamud's still descending even though we beat van Darnus!" they did in 1.x. Make the failure be our direct fault because we finally found an enemy we couldn't overcome.
... I doubt it'll happen, but I can dream.