There was a bug/inconsistency in email handling. This has been corrected. pretalx now follows this logic:
If only an event email address is set (which is mandatory), but no sender address in the mail settings, the instance-global sender address is used (e.g. "MyEvent email@example.com). The Reply-To is set to the event email address.
If a sender address is set, it is used as the sender and no further Reply-To is set. This naturally works best if the "custom mail server" option is checked, but it is not mandatory.