Running play and the umpire throwing a defensive holding flag?
It could happen. A pull and shoot, a hold to keep a guard from pulling or a center being held to prevent him from getting to the next level all come to mind.
I think the flag was for the attempt to keep the center from going to the next level but I think that could be debated on whether it was a material restriction or not.
That said, I'd enforce this from the end of the run. Getting technical about whether the hold occurred before or after the hand-off is pointless and rewards the defense. The hold may also have started at the snap but it continued on throughout the play.