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.
Also some people use annotations for runtime checks or even for things unrelated to typing. I think it would be a pity to lose these functionalities for small performance gains.

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Ivan