Just downloaded Myst IV:Revelation offline installer, installed it, when I launch it Windows Defender detects C:\GOG Games\Myst 4\bin\Myst4.exe as being Trojan:Win32/Zpevdo.A and quarantines it ? Anyone else encounter this?

I don't have the game but it's most likely a false positive. In these cases, the best thing to do is scan the file on VirusTotal, or search its hash/checksum in the Search box.

uploaded the file to virus total & it got 12/67 hits

That's a very weird behavior. It's probably due to the measures taken to disable the SecuRom/DRM, or the traces of the DRM itself.

That's clean. All those that detected it are not trustworthy, IMO, and Symantec/Norton being well know to generate false positives so many times. If something is not detected by Kaspersky, Bitdefender and Eset, then it is pretty much safe.

Might I also throw ClamAV into that ring of trust?

I've never used it myself but feel free to do it. I'm sure there are a few lesser known AV companies that have solid products.

I can confirm this, my Myst 4 executable was moved to quarantine by Windows Defender too.