We are having some random issues with Direct Access Clients that are registered with a global IPv6 address. Found an old blog post that point to the same issue: https://www.ivonetworks.com/news/2011/11/client-side-ipv6-and-directaccess-dont-always-get-along/

Also found some forum discussions of more recent date that mentions the issue: https://social.technet.microsoft.com/Forums/office/en-US/7227bf85-dc3c-4fa2-9245-371e1613cae2/directaccess-iphttps-tunnel-with-native-ipv6-client?forum=winserverNIS https://social.technet.microsoft.com/Forums/office/en-US/c4ed2233-8f08-4e56-a7f0-1bd56665c407/directaccess-with-clientside-ipv6?forum=winserverNIS

We are experiencing the same issue, but some of the Direct Access Clients with “Native IPv6” are connecting fine. For the time being we are deactivating IPv6 for the NICs on the affected clients by unchecking the check box for Internet Protocol Version 6 (TCP/IPv6). I will update this blog post if we find the cause (according to MS Client-side IPv6 is supported).