I dont have much experience with global protect and cleint VPNs on the Palo Alto. I have had similar problems with Anyconnect and an ASA.
For the users that you are having issues connecting to, what is the subnet of their local network? Does it overlap with one of the networks that should be tunneled through global protect? If there is an overlap, your server will know how to get to the user device, but the user device will then try to respond on the local network. When you change the prefered ip, the user device then sends traffic over the vpn. Once you do this, does the user device loose access to other devices on thier local network. In a command prompt on the user device you can run "route print" to show you what routes are on the computer and the gateway for each route.
I have seen this happen with users that connect directly to a comcast router. They get a 10.0.0.0/24 address. We used to use 10.0.0.0/16 for devices on our network. They would have issues getting to those first 254 addresses.
Matt
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