Just off the top of my head, here's some setting assumptions D&D makes thats not even universal to high fantasy, let alone dark/low fantasy, historical settings, urban fantasy, or scifi;
Magic is something anyone can access with proper education and time
There is a pantheon of very real deities who each have different purviews and distribute magic
Combat is generally slow and grindy, and your average player character or enemy can take multiple strikes from a sword and keep fighting.
Characters will get physically stronger and more martially competent as they continue to adventure, to the point of being able to fight enemies like dragons and giant demons.
Magic takes the form of a specific list of flashy and powerful effects, most of which can be performed in the span of seconds and are oriented around combat.
There is an afterlife and people can be revived
Generally speaking a character is going to have to choose between martial prowess, magical capability, and a sort of "everything else" bucket. In particular, a character specialized for combat is going to have little to do outside of it.
Some of these assumptions (leveling up, grindy combat, characters specializing in combat/magic/noncombat) are both very restrictive in the kinds of stories you can tell, and fundamental to how Dungeons and Dragons works to the point that you lose the benefit of familiarity if you try to remove it. (Good luck selling "We're playing 5e but we're not leveling up" or creating an entirely different suite of classes)
I saw someone compare D&D to Star Wars, which is more or less the most popular "scifi with magic" media; Jedi just don't fit into D&D classes; they're the biggest source of player-side magic, and their powers are a small toolkit of subtle, new-age-mysticism tricks; pretty far from wizards, clerics, and warlocks.
I know 5e-Only types will mostly not care but for the sake of my sanity I need this written down.
Yes, you can in fact play D&D 5e with a scifi skin! The catch is though, if you do that, you will just be playing D&D 5e with a scifi skin.
That's the Rule Zero Fallacy. The fact that you can ignore any rule that exists, ever, doesn't mean it doesn't exist.
You can use D&D to play any sort of game if you just ignore all the rules, exactly as you can use solitaire to play a tense political scifi game if you want to. You're still trying to use a hammer to saw off a plank.
Meanwhile there is very likely a game that actually does what you want it to do without having to ignore or rewrite the whole game to make it work.
(with smug confidence) yeah the game is great if you throw out half the components and do a ton uncompensated game design for free. i think it's funny that that's not obvious to you.
