Number eight Billy Vunipola re-fractured his arm in Saturday's 23-12 loss to the Springboks in Bloemfontein which meant the home side clinched the series 2-0 with a game to spare.
He spent four months on the sidelines this year after breaking his arm in a European Champions Cup tie for his club Saracens, and was forced off again on Saturday before halftime.
Prop Mako Vunipola is heading back to England for family reasons by prior arrangement with team management, while Genge sustained a knee injury in training.
Exeter Chiefs' Alec Hepburn has been called up as a front-row replacement.
News that makes sense
Your trusted source for staying up-to-date with the world around you. Get free daily news updates and analysis, straight to your inbox.
Hepburn, 25, has two caps, both in this year’s Six Nations, and will link up with the squad at their training base outside Durban ahead of the final test in Cape Town on Saturday.
The Boks could inflict a sixth test defeat in a row on Eddie Jones’ ailing side.
England have not lost six tests in a row since they went on a seven-match losing streak in 2006, though they made the World Cup final the following year, losing to South Africa.
(Reporting by Nick Said,; Editing by Ed Osmond)
