Munster centre Jean de Villiers was one of six overseas-based players named in the Springbok matchday squad for next month's Millennium Stadium encounter but the 29-year-old has today been ruled out with a shoulder injury.
De Villiers has agreed to return home to South Africa to improve his World Cup prospects after just a single season in Ireland but he will now miss out on what could have been a special European swansong.
Few details have been given as to the extent of de Villiers' injury so it as yet unclear whether he will be available for the single Test against France on June 12 or the double header with Italy on June 19 and 26 prior to the start of the Tri Nations on July 10.
De Villiers' replacement for the Cardiff showdown a week on Saturday will be one of the form players in the Southern Hemisphere.
Stormers centre Jaque Fourie has produced some sensational displays since his move from the Golden Lions last summer, helping his new side power into this weekend's Super 14 Final.
The 27-year-old broke Lions' hearts 11 months ago when he crossed for a crucial score with just minutes of the second Test remaining in Pretoria.
Until that point, the Lions had looked set to level the series but Fourie's fine individual intervention changed the course of history.
Worryingly for Wales, Fourie has an outstanding scoring record in Springboks colours having registered 28 tries in his 54 caps.
Fourie comes straight into the Bok starting XV for the Wales game, with uncapped Stormers team-mate Juan de Jongh remaining on the bench.
Revised South Africa squad to face Wales, Millennium Stadium, June 5
15 Francois Steyn (Racing Metro) - 36 caps
14 Gio Aplon (Vodacom Stormers) - uncapped
13 Jaque Fourie (Vodacom Stormers) - 54 caps
12 Butch James (Bath) - 35 caps
11 Odwa Ndungane (Sharks) - 6 caps
10 Ruan Pienaar (Sharks) - 36 caps
9 Ricky Januarie (Vodacom Stormers) - 40 caps
8 Joe van Niekerk (Toulon) - 51 caps
7 Dewald Potgieter (Vodacom Bulls) - 1 cap
6 Francois Louw (Vodacom Stormers) - uncapped
5 Andries Bekker (Vodacom Stormers) - 21 caps
4 Danie Rossouw (Vodacom Bulls) - 46 caps
3 BJ Botha (Ulster) - 19 caps
2 John Smit (Sharks, Capt) - 93 caps
1 CJ van der Linde (Leinster) - 58 caps
16 Chiliboy Ralepelle (Vodacom Bulls) - 8 caps
17 Jannie du Plessis (Sharks) - 12 caps
18 Alistair Hargreaves (Sharks) - uncapped
19 Ryan Kankowski (Sharks) - 11 caps
20 Meyer Bosman (Vodacom Cheetahs) - 3 caps
21 Juan de Jongh (Vodacom Stormers) - uncapped
22 Bjorn Basson (Vodacom Cheetahs) - uncapped