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The Wallabies captain failed to complete training on Thursday night after corking his leg in last weekend's 25-17 loss to the Lions in Johannesburg.
Brumbies coach Andy Friend has opted to start Gene Fairbanks at inside centre, with Tyrone Smith replacing Mortlock at outside centre.
The Brumbies, sitting precariously in ninth spot on the table nearing the halfway point of the competition, enter the round-seven fixture at ABSA Stadium in an eerily similar position to the last time they took on the Sharks in Durban.
On that occasion, two years ago, the Sharks were riding a nine-match winning streak at home and Mortlock was scratched after breaking his hand the previous week in a first-up tour loss for the Brumbies in South Africa.
But the Brumbies outfit rallied to post an against-the-odds 21-10 boilover.
The Sharks are now on a seven-game home winning streak and have lost just one of their last 10 matches in Durban since falling to the Brumbies - the 2007 final heartbreaker against the Bulls.
Coach Friend on Friday said the Brumbies were bracing for a bruising and frenetic encounter against the second-placed Sharks.
"`Everything they do, they do it at real pace and real purpose,'' he said.
"They run hard, they tackle hard, they clean out hard and they scrummage and lineout hard.
"So it's going to be a very torrid affair.
"And given that they're just back from (their four-match Australasian) tour and in front of their home crowd, they're going to want to please them and show the form they showed on their road trip wasn't a fluke.
"So it's going to be a pretty full-on trip.''
The Sharks netted three wins in Australia in New Zealand, finishing with an impressive 22-10 victory over the Force.
Friend said he didn't buy into the theory the South Africans may be travel weary.
"Coming back from Perth, sitting in a comfy seat for 12 hours, I don't think that really fatigues you,'' he said.
"It's a big challenge for us more than anything, given that we lost our last game and we want to prove that we are better than that.''
Despite losing to the Lions, the Brumbies still boast one of the best records in South Africa of the nine Australasian franchises, having won 11 from 21 in the Republic since 2000.
And all six previous matches played between the Brumbies and Sharks in Durban have been determined by margins of 12 points or less, as have the last six played between the sides at all venues.
