Personally I don't want a game where Russia, Austria, and the Ottomans are laughably impotent and unable to expand to their historical extent, which is what you always saw in EUIII 1399. It just doesn't feel like the early modern period to me without these states being superpowers.
Honestly 1453 is the best possible start year by an enormous margin. It avoids the HYW issue that taints English games, it puts all the historical great powers in a perfect position, and it is probably the most widely-accepted proposed starting year of the early modern era. Literally the only reason not to start at 1453 is Byzantium. And don't get me wrong, I've played me quite a few Blurple games in my day, but if we're talking historical plausibility here, the Byzzies were such a rotting husk of their former glory by the mid fifteenth century that including them almost feels wrong. They were a medieval power rooted in classical origins, and in this era they're just laughably out of place. More than that, they were the last remnant of Europe's first great civilization, and their death facilitated the rise of its second. It was literally an epochal event for Europe that set most of this period's narrative into motion. That's the sort of thing you want preceding your start date.
Of course I could just start at the 1453 start date, but I just feel dirty and weird not playing the grand campaign.