Which Assassin's Creed game was the first to feature the city of Constantinople as a major setting?

Assassin's Creed: Revelations was the first Assassin's Creed game to feature Constantinople as a major setting.

Released in 2011, Revelations follows Ezio Auditore as he travels to Constantinople in the early sixteenth century. The city is divided by the Golden Horn and includes districts such as Constantine, Bayezid, Imperial, and Galata. Ezio investigates Altaïr's legacy while becoming involved in an Ottoman-era conflict.

The game also returns to Masyaf and includes sequences set during Altaïr's life. Its structure therefore links the first game's protagonist with Ezio, making it the conclusion of Ezio's main trilogy and a bridge between two generations of Assassins.

Constantinople was the historical name used in the period depicted by the game. The city is now generally called Istanbul, a name that became official in international use during the twentieth century. Revelations is set centuries before that modern naming convention, which is why the historical name appears in the title and setting descriptions.