Richard III sought a marriage with a spinster Portuguese infanta after his wife and son died. But before his son, Edward of Middleham, Prince of Wales, had died, there had been talks about the marriage between young Edward and Isabel of Aragon, eldest daughter of the Catholic Monarchs.
I’m unsure if there was any further talk of the match once Edward had died in March/April 1484, since Richard only made the announcement at his Christmas-court that he and Anne had been advised against further conjugal relations.
Now, Isabel would be 15 when Anne Neville died – young, but not immensely so by 15th century standards – to become queen of England, and there were enough younger sisters who could take her place as the future queen of Portugal.
The only objection I could maybe see is that of the mother of the bride: she reportedly hadn’t yet shaken off the scorn that her own prospective marriage to Edward IV had been trashed by his marriage to a “widow of England”. However, the same Edward IV, from what I can find, seems to have been in talks to wed Edward V to the same Isabel. Although, once the future duchess of Brittany entered the market, said talks ground to a halt.
So, what if Isabel of Aragon had been married to Richard III? The POD might not butterfly Henry Tudor’s invasion or Bosworth, but an alt-Bosworth might not be so decisive, or perhaps Henry gets killed instead of Richard.
I agree that it is a far reach from Bosworth – August 1485 – to Isabel becoming heiress in December 1497, but I don’t think it’s necessarily butterfly-genocide if events in Spain run close to/as OTL. But let’s remember that if anyone had predicted in 1496 when Isabel married Manuel of Portugal, and her brother and sister married their respective Austrian spouses that her Burgundian nephew would inherit the Spanish realms, they would’ve probably been tried and burnt at the stake by the Inquisition.