City's problems in central defence have been well documented after losing key players to injury and the Brazil international has been doing a fine job when dropping back from midfield to fill in.
However he was sent off after being booked twice in the 3-0 Premier League win over Aston Villa on Saturday and will now miss the clash against Saints.
City will also be missing midfielder Rodri, who has a hamstring injury, while left-back Oleksandr Zinchenko, centre-back Aymeric Laporte and winger Leroy Sane, all remain on the sidelines with knee injuries.
Boss Pep Guardiola will use the game to give some of his fringe players a run out, but it will still be a very strong side that takes on the struggling Saints.
Teenage defenders Eric Garcia and Taylor Harwood-Bellis could get their chance given City's shortages at the back, while Angelino will hope to start at left-back after coming off the bench on Saturday.
With Rodri sidelined as well as Fernandinho, Guardiola will have to decide whether to retain Ilkay Gundogan in midfield or rest the Germany international.
Southampton boss Ralph Hasenhuttl is likely to shuffle his pack significantly after the record 9-0 Premier League home defeat against Leicester on Friday.
Left-back Ryan Bertrand is banned after being sent off against the Foxes, but the changes are unlikely to be restricted to just one.
The Saints will definitely be without injured duo Cedric Soares, who has a calf injury and Moussa Djenepo, who will miss out with a hip problem.
Tuesday night's clash will be the first meeting of the week between the two sides as Saints also have to travel to the Etihad Stadium in the Premier League this weekend.
Following the mauling against the Foxes, the double-header against City is probably the last thing that Hasenhuttl and his side need.