As discussed on Matrix:

• this should not check for key existence but rather non-falsy values
• _validate_config after _postprocess_config would be a good place for this

Also, I'd consider these options required since things will be broken if they are missing:

SQLALCHEMY_DATABASE_URI
SECRET_KEY
BASE_URL

CELERY_BROKER
REDIS_CACHE_URL

DEFAULT_TIMEZONE
DEFAULT_LOCALE

CACHE_DIR
TEMP_DIR
LOG_DIR

STORAGE_BACKENDS
ATTACHMENT_STORAGE

SUPPORT_EMAIL  # error reports
NO_REPLY_EMAIL  # noreply sender

Some of them have decent defaults that work in a standard environment, but they are nonetheless required, so if someone set them to an empty string, None, etc., things would break.