Matilda of Tuscany was a powerful figure in the Investiture Controversy. Heiress to her father's vast estates she was reputedly intelligent, forceful, pious and well educated, and managed to resist Henry's ambitions in support of the Papacy. At her death her lands were willed to the Papacy, as she had no heirs.
So, what if she was male? Assuming she marries (who?) and has a kid, how does the presence of a powerful landed vassal in Italy affect developments? Could he or his son claim the Iron Crown, perhaps?