Opener Stiaan Van Zyl has been dropped by South Africa and Dale Steyn has been ruled out of the fourth Test with England, which starts on Friday, live on Sky Sports.
Van Zyl, who is usually a middle-order batsman, has scored just 69 runs in five innings in the series, at an average of 13.80.
The uncapped Stephen Cook - son of Jimmy Cook, a prolific run-scorer in county cricket - will make his debut in Pretoria.
Cook, 33, scored an unbeaten 53 playing for South Africa A in a warm-up match with England, which the tourists won by an innings.
Fast bowler Steyn has been ruled out as the Proteas seek to give him more time to recover from a shoulder injury ahead of the five-match one-day international series starting on February 3.
A Cricket South Africa release said: "Dale Steyn has not recovered from a shoulder injury and will not be available
for selection for the last Test, and all efforts will be made to have him ready for the one-day international series starting at the end of the month."
Wicketkeeper Quinton de Kock will have a final assessment on his troublesome knee on Wednesday.
De Kock was injured while walking his dog on the eve of the third match at the Wanderers and replaced in the side by Dane Vilas.
England have won the Test series after taking an unassailable 2-0 lead ahead of the final match at Centurion Park.
South Africa: AB de Villiers (c), Kyle Abbott, Hashim Amla, Temba Bavuma, Stephen Cook, Quinton de Kock (wk), JP Duminy, Faf du Plessis, Dean Elgar, Morne Morkel, Chris Morris, Dane Piedt, Kagisa Rabada, Rilee Rossouw, Hardus Viljoen.