When "Break comments into pages" and "Enable threaded (nested) comments" in Settings > Discussion, if you try to reply to a comment and hit the post comment button, WP gives "Page not Found".
The comment is actually recorded in the database, but it is not nested underneath the comment you wanted to reply to.
This error comes up with several themes and with the original TwentyTen delivered with WP 3.0.4 as well.