Dominion
I don't think the fact that Nginx solved the issue means that the browser/OS was not a factor in play. It was reported disproportionately with Safari, that being the browser which was late to the game in http/2 adoption.
I think this is what probably fixed it for some people:
*) Change: the "421 Misdirected Request" response now used when
rejecting requests to a virtual server different from one negotiated
during an SSL handshake; this improves interoperability with some
HTTP/2 clients when using client certificates.
http://nginx.org/en/CHANGES
though I would agree that it seems people may be trying to group together general "Oops!" issues that are likely having differing sources in fault.
A couple of questions for people still having this issue. Are you:
1, using http/2
2, using SSL/TLS certs
?