config will only not load missing settings from setting table / over-rides unless it is NULL

Steps
1) instantiate a domain / site - set customUploadDir through php overrides in the settings file
2) ensure the customUploadDir is not set on the $config object
3) if the customUploadDir is defined in a setting OR php override but not in the $config object you will see
"Check Settings
customFileUploadDir has an incorrect directory path. Please go to the path setting page and correct it."

The reason being the code to load settings from settings is only called if NO config variables are set
https://github.com/civicrm/civicrm-core/blob/master/CRM/Core/Config.php#L448

The particular item is a bit edge case / hard to define many situations where it would arise - but the general problem - config items not necessarily loading from settings into the prefetch object is likely to cause other unpredictable behaviours