The Save button in Special:Preferences is supposed to only be greyed out until you change something. It remains greyed out if you only change the email blacklist at "Prohibit these users from emailing me" under "User profile", or the muted users at "Do not display notifications from these users" under "Notifications".
The Save button works if you also change another preference, but returns to greyed out if you change the other preference back before saving.
Tested in Firefox, Chrome and Edge at the English Wikipedia in Vector and MonoBook.
It was reported at https://en.wikipedia.org/w/index.php?title=Wikipedia:Village_pump_(technical)&oldid=836235277#Unable_to_edit_Preferences