A simple example that occurs naturally in set theory (although it is not as mysterious as the one in Asaf's answer and there are probably no more open problems about it) is the set $\mathbb{R} \cap L$ of all constructible reals. If $V = L$ then of course this set is uncountable, but the statement "$\mathbb{R} \cap L$ is countable" can be proved consistent relative to $\mathsf{ZFC}$ by forcing, and it also follows from large cardinal axioms (for example, from the existence of a measurable cardinal, or just from the existence of $0^\sharp$.)
The statement "$\mathbb{R} \cap L$ is countable" is equivalent to the statement "every $\Sigma^1_2$ set of reals with a $\Sigma^1_2$ well-ordering is countable," where $\Sigma^1_2$ denotes the pointclass of projections of co-analytic sets.
There is an open problem along these lines about a pointclass much bigger then $\Sigma^1_2$:
Does any large cardinal axiom imply that every $(\Sigma^2_1)^{\text{uB}}$ set of reals with a $(\Sigma^2_1)^{\text{uB}}$ well-ordering is countable?
Here $\text{uB}$ denotes the pointclass of all universally Baire sets of reals, and a set of reals $A$ is called $(\Sigma^2_1)^{\text{uB}}$ if there is a formula $\varphi$ such that $x \in A \iff \exists B \in \text{uB}\,(\text{HC};\in , B) \models \varphi[x]$ for every real $x$. Essentially the question asks whether there is a large cardinal axiom that transcends the pointclass $(\Sigma^2_1)^{\text{uB}}$ in the way that $0^\sharp$ transcends the pointclass $\Sigma^1_2$.
For technical reasons, let's strengthen the notion of "$(\Sigma^2_1)^{\text{uB}}$ well-ordering of a $(\Sigma^2_1)^{\text{uB}}$ set of reals" to "$(\Sigma^2_1)^{\text{uB}}$-good well-ordering," by which we mean that the well-ordering has length $\le \omega_1$ and the set of reals coding its proper initial segments is a $(\Sigma^2_1)^{\text{uB}}$ set. It is consistent (as shown using forcing) that all such well-orderings are countable.
If there is a proper class of Woodin cardinals (a fairly mild large cardinal assumption,) then there is a canonical $(\Sigma^2_1)^{\text{uB}}$ set of reals that is maximal under inclusion among $(\Sigma^2_1)^{\text{uB}}$ sets of reals admitting $(\Sigma^2_1)^{\text{uB}}$-good well-orderings.
This canonical $(\Sigma^2_1)^{\text{uB}}$ set of reals can be thought of as a higher-order analogue of $\mathbb{R} \cap L$, and the question asks whether any large cardinal axiom implies that it is countable. A "yes" answer would be a very important development for the field of inner model theory.