Smith's ankle flared up during Pakistan's three-wicket win on Thursday, officials said. As a result, he was unable to field for the majority of the Pakistan innings and a decision on leaving him out of the decisive match in Benoni will be made on Friday.
"Graeme's chronic left ankle problem has surfaced again during this ODI Series. We have been trying to manage him but unfortunately it slowed him down today," team manager Mohammed Moosajee said.
"As things stand, he is unlikely to play in the last ODI. He had surgery on this ankle a while ago and I think the load and the volume of cricket for the year and particularly during this ODI series has troubled him," he added.
South Africa and Pakistan are level at 2-2 in the five-match one-day series, which serves as a warm-up for the Champions Trophy in England in June.
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