I'd like to see a fantasy/sword & sorcery setting with an actual low-magic casting system.
Bounded accuracy makes 5E's core translate very well to low-magic settings. I was hoping for variant magic systems in Thule and AiME but no such luck.
I've been toying with an idea.
The core of it is that you're not just trying to keep your character alive, but to retain control of it: madness, addiction, obsession, possession, and the like can cause you to loose control of your character even if it doesn't die. Aside from a CoC style sanity score, and rules for highly-addictive 'healing potions' or 'black lotus' that might do in any character, casters could face a particular danger in that line:
Warlock: I'll take the low-hanging fruit, first.

Obviously, a Warlock imperils his soul by making an infernal pact, make use of infernal powers carry that risk, mechanically, the more you use spells & even Eldritch blast, the greater the risk your Patron takes over. Star Warlocks could 'just' be risking their sanity.
Sorcerer: Taking a page from the playtest sorcerer, you have magical power from a supernatural ancestry, as you embrace and develop that power you start to take on ancestral traits - if that transformation progresses too far, you become that type of monster, losing the character (which may become something the surviving party must deal with).
Wizards: Harkening back to the early days of the game, and to it's Vancian inspiration, then ratcheting it a bit further: mastering wizardry takes decades of study and devotion, to succeed in becoming a wizard you not only have to be intelligent, you have to be dedicated and determined to the point of obsession. Each spell you master deepens that obsession with arcane knowledge and power, when you cross that final line, you simply no longer have any interest in adventuring or anything else... you engage in arcane study & experiment to the exclusion of all else, eventually dying (perhaps of hunger/thirst/neglect) and becoming a lich without even realizing it...
Clerics/Paladins: If the gods aren't so nice or are very demanding of their worshippers' obedience, Cleric might not even be a playable class. Or, rather than clerical magic carrying with it a risk of losing the character, every little act of free will or deviation from dogma or crisis of faith involving the use of divine magic could risk losing that power forever.
Druids could risk losing their connection to civilization and humanity, wandering off into the wilderness, never to return, or getting 'lost' in an assumed shape and staying becoming that animal for the rest of their lives.