I think any homebrew would include "personalization" and "investment" as things that any published setting would lack. Even if a game would appear little different from the FR to a truly independent observer, those two things change the enjoyment level intensely.
To reiterate, I've nothing against the Realms; I simply prefer homebrew, and make some different choices. But if specific points of variation are useful data, then:
- More focus on the martial, less focus on the arcane. Wizards and their ilk can be interesting characters for sure, but overall they have no particular positions of prominence in the overall setting's themes.
- Deities draw power from what they represent, not from worship. The god of justice grows stronger if abject agnostics or even atheists act to further justice, or grows weaker if zealous worshippers spread injustice throughout the land and call it "justice."
- No deities of mortal origin. Purely personal preference.
- Not as much emphasis on some of the more gently romantic thematic elements. Elves and cats and silver and moonlight and bardic music and things like that. I totally respect their inclusion, and am not trying to be contemptuous here: I think it's awesome that a fantasy world can go for that romantic side. But most of my players (including my wife) are more dwarf-metal or gnoll-tribal than elf-lyricism at heart.
- More customized monster palettes. I don't really use beholders, mind flayers or drow, for instance, and I like "gnome" to mean "earth elemental."