I currently have nothing physically connected to input 2, gain is at zero. Yet in Cubase input 2 shows signal when PC audio is present (example: if Spotify is playing). Its very low level (-80dB or so) but this doesnt make sense. Again, nothing is connected to input 2 and input 1 does not show this leaked-through signal.
Very odd.
Input 2 has an Hi-Z mode, not present on Input 1.
I’d bet good money that this mode is engaged, and if you disengage it, the noise will disappear.
Any unconnected Hi-Z input is susceptible to pickup EMI radiations, and your PC is just leaking EMI. Just moving your mouse or displaying a fast action video might also produce audible noise with an open nearby hi-z input.
It’s like when a guitar amp was picking a local taxi CB line… if you were born <1970 you know what I’m talking about… 
Your UR22C is not at fault here, but your PC might be a bit “leaky”, EMI-wise. (or the speakers or cables or ??)
Personal note: I need to disconnect my printer before recording because its PSU is leaking EMI so badly, it’s picked up even on some microphone’s pres… I scratched my head a while before I found the culprit…
Its a good thought, but that was one of the first things I checked and Hi-Z is not on. Moreover, the detected signal is only present when another app is playing audio… and in fact it is that audio which is showing up on Input 2 (so its not EMI).
To prove it I just did an experiment: With Spotify playing a song, I recorded input 2 in Cuebase (again nothing connected to that input). And what I found is that I had recorded exactly what Spotify was playing (at an extremely low level mind you, but when I boosted it and turned my monitors way up, there was no mistaking it).
So the question is, is this an issue with the driver or is it in the hardware?
I don’t follow the reasoning of your tests. Is there any volume difference when enabling/disabling hi-z?
Another track could be “conductive emissions”. Can you test plugging the interface via a usb hub? and/or a diff. port?
I just cannot imagine a driver/software cause for this.
My 3rd and last hypothesis would involve calling an exorcist, and it would be too complicated with this covid thing… so we won’t go there.
No difference whether HiZ is on or not. I cant imagine its software either. More likely a flaw in the hardware design which is allowing output to leak through to that input. Looking at the signal flow chart, it could be an issue with Mix 1 where output from the PC is combined with the hardware inputs.