Dragons hooker Elliot Dee had been flown out as cover for Lake, who Wales say has come through two training sessions.
Lake, 27, is in line to continue his record as the only Wales player to start every Test under Tandy.
Following the 39-24 win against Fiji, Rees-Zammit and Edwards were left out of the starting side against Argentina for Scarlets duo Ellis Mee and Sam Costelow, who in turn have been omitted from the squad against South Africa.
There is a new-look centre combination in Durban with Cardiff’s Thomas partnered in the midfield by Llewellyn.
Eddie James is not included in the squad while Hawkins will drop to the replacements bench, where he will also cover the fly-half position and the backline.
Ospreys scrum-half Reuben Morgan-Williams comes in for team-mate Kieran Hardy on the bench.
Mann, who missed out against Argentina, returns to the blind-side flanker role alongside Jac Morgan and Aaron Wainwright.
Reffell is set to make his first international appearance for a year, and his first selection by Tandy, after being left out of the previous two campaigns.
“We’ve made some changes to the starting side,” said Tandy.
“It’s coming to the end of the season and we’ve had a big bit of travel.
“Some boys deserve an opportunity and it’s a chance to freshen up the team.”
Cardiff lock Williams, who will partner Adam Beard, makes his first Test start for a year.
With Carter sidelined, Wales face the Springboks without the lock pairing that finished the Six Nations with Exeter captain Dafydd Jenkins missing the summer tour because of a shoulder operation.
Carter forced his way into the starting line-up for the final three games of the Six Nations and continued in the side for the uncapped fixture against the Barbarians and Nations Championship games against Fiji and Argentina.
The absence of the 21-times capped Dragons forward further stretches the second-row resources.
Flanker Plumtree covered the second row in the fixture against Fiji and Thomas was called to South Africa as cover and now finds himself thrust into the 23-man squad.
Wales complete the season against a team that defeated Tandy’s side 73-0 at the Principality Stadium in Cardiff in November 2025.
Wales have won three and lost eight of the 11 internationals so far in Tandy’s first season in charge, with a victory and defeat so far in the Nations Championship.
“South Africa are world champions and have loads of depth,” said Tandy.
“For us, it’s about putting our game out there. We want to see a real physical edge.
“We’re going up against probably the most physical team in the world.
“It’s a great opportunity to test ourselves against the best team in the world.”