1. It looks like there is still a room for performance improvement of typing w.r.t. how ABCs and issubclass() works.
I will try to play with this soon. (the basic idea is that some steps could be avoided for parameterized generics).
2. I am +1 on having three separate options to independently ignore asserts, docstrings, and annotations.
3. I am -1 on ignoring annotations altogether. Sometimes they could be helpful at runtime: typing.NamedTuple and mypy_extensions.TypedDict are two examples.