There's quite a few PoDs. Where and when it happens matters considerably.
One could use a late antiquity PoD- have Majorian succeed in his African conquest, and his heirs keep on to Italy at worst (I would go with a surviving WRE reduced to Italy, North Africa, Hispania, and the rump of Provence/Septimania and Illyria, potentially being usurped, conquered, or collapsing later, leading to a Chinese-esque cyclical process). Or you could go with a successful Justinian with the WRE/Italy breaking off. Or the Goths being more successful and forming a Gotho-Roman "kingdom" a la the Franks in Gaul.
The easiest way is to go back to pre-HRE days, either before or after Charlemagne. There are at least two timelines on this site- Carps Sons of the Harlot Empress, and Mario's Bernardians. This means a wildly divergent European history, as it means the Pope is the King/Emperor's vassal, to say nothing of divergent histories in eg the Frankish partitions, the Norman diaspora, the collapse of the Andalusians, the Byzantines, etc.
In the High Middle Ages things are tricky. The two that come to mind are Matilda of Tuscany being born male or having an heir, or something involving the Hohenstaufen. Either avoid Henry VI's premature death, or Philip's assassination; the most likely result of this is a High Medieval Habsburg, with a Sicilian (and *Spanish? Frederick was married to an Aragonese Princess, and this is at the cusp of the Reconquista, also the 4th Crusade... plenty of options for expansion) branch under Frederick II and a Swabia-based Imperial dynasty (with Milan?) crushing the Papacy between them. I've actually thought about the latter- my general thought was that Sicily annexes Greece, Catalonia (including Provence), North Africa, Egypt &/or Jerusalem (nominally and/or temporarily, at best until the Mongols, at worst like OTL's Frederick II's claims), and the entire Papal States, the HRE/Germany centralizes around Swabia-Austria-Pomerania (the Northern Crusades being used, potentially, by a strong German monarchy in a manner similar to the Albigensian Crusade), and Northern Italy, including the rather disaffected rump of Venice, pulls a Switzerland and confederates the Lombard League. France, caught between super-Germany with the Rhineland/Low Countries, and the English on the other hand, is left sulking in a corner.
Later on the Visconti are an excellent candidate (hint hint), as they came quite close to conquering all of the north OTL, and have an excellent window of opportunity with both the Papacy and the Empire weak.
There are other possibilities- Irene is doing a timeline with Venice scooping up most of the north, and it's not unthinkable that 15th or 16th century Venice could have annexed the Romagna and/or Lombardy. There's also, I think, a Cesare Borgia timeline. You could also do something hilarious like have a Habsburg branch gain Naples+Milan, (re)conquer the Venetian Terrafirma, and inherit Tuscany, Savoy, Mantua, Ferrara, etc, before finally getting the Italian Crown from their cousins at an alt-Vienna or alt-War of the Austrian Succession or whatever. That would be very difficult, though, owing to the lack of interest by any powers for a united Italian state; still, not impossible, and it would make for a fun read if done right.