happens to me too. I think it started after one of the recent OS updates.
I'll click to close a tab in Safari and it won't register the click. So I either keep clicking which does nothing, or I have to move my mouse away slightly then move it back to the little 'x' and then it finally works. Very annoying. Same thing happens when I go to close a window by clicking the red x in the top left.
No idea how to solve it.