Manuel tossed for two touchdowns, completing 27-of-35 pass attempts, and carried the ball 12 times for Florida State (4-0, 2-0 ACC).
Chris Thompson rushed for 103 and two TDs on 15 carries and James Wilder Jr. also scored twice for the Seminoles.
Clemson (3-1, 0-1) lost despite a three-touchdown performance from Tajh Boyd, who passed for 237 yards on 20-of-36 efficiency and also ran the ball 18 times for 44 yards.
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