The Borussia Dortmund veteran missed his side's first two League A Group 3 fixtures due to illness and has now been ruled out for the rest of the month owing to a muscle tear.
Hansi Flick otherwise has no concerns for matchday three, but Nico Schlotterbeck is walking a tightrope after picking up a yellow card for his clumsy tackle on England's Harry Kane.
Schlotterbeck would miss the impending showdown with Italy if he is booked here and may therefore cede his spot to Niklas Sule, with Antonio Rudiger continuing at the back.
Lukas Klostermann and David Raum did not do a lot wrong in the recent draw with England and will hope to hold their places, and the same can be said for Joshua Kimmich.
Ilkay Gundogan may cede his spot to Leon Goretzka, though, while Thomas Muller should start for what would be his 115th appearance for the national team.
Jamal Musiala has put his name in the hat for another start over Leroy Sane, but the need for fresh legs in the attack could see Serge Gnabry displace Jonas Hofmann, despite the latter's well-taken goal on Tuesday.
Flick ought to prepare his side for a true battle of physicality on Saturday, which could therefore see Kai Havertz given the nod up top ahead of Timo Werner once more.
Germany possible starting lineup: Neuer; Klostermann, Sule, Rudiger, Raum; Kimmich, Goretzka; Gnabry, Muller, Musiala; Havertz