Looking back at the Athletica opinion, the 6th followed the Supreme Court in referring to Skidmore as "the power to persuade", as distinct from "the power to control". There's an abstract rubric for courts to use in assessing agency interpretations that don't have the force of law. But the door is very much left open for courts to adopt interpretations they find more thorough, better reasoned, more consistent, &c. You could squint and see an outline of how appeals courts review all decisions there.
With "presumption", I think you may be confusing terms. There's a statutory presumption you get in your favor once you successfully register copyright with the Copyright Office. That's a presumption for a party challenging the validity of a copyright to overcome---say, a defendant in a copyright infringement suit. Judges and courts don't bear "burdens" under "presumptions". They follow the rules that put them on litigants, or review the decisions of lower courts that should have.
Consider the opposite case where the Copyright Office refuses registration because it says the subject matter's not copyrightable. Perhaps because the artist created the artwork by prompting Midjourney. There's an appeal process for refusal to register within the Copyright Office, under its regulations. If you appeal twice and lose twice there, that's "final agency action" courts can look at.
If the issue ends up in court, the statutory presumption of 410(c), by its terms, doesn't apply. No issued registration, no presumption of validity. But there is still Skidmore. In the Sixth Circuit that's clear now. The court couldn't ignore the Copyright Office's reasons. But if it weren't persuaded, it could rule otherwise. It would have to read the Copyright Office and grapple with it, but not agree with it. Especially if it heard a better argument in briefing.