Do you have something in mind?
I don't see much difference. After all, all that would change is that she would rule together with Phillip the fair rather than being "regencied", and she would still likely heed her father's advice regarding the ruling of the kingdoms. Charles would still be the heir.
Her personal situation would have been less cruel and tragic, but i don't see any consequence that would trascend that.
Maybe the Comunidades rebellion could be butterflied away, if Charles was brought up in Spain rather than in Flanders?