The real-life Frank that runs over Donnie's girlfriend is Elizabeth's (Donnie's sister) boyfriend. We see him drive past Donnie at the start of the movie after dropping her off at home shortly before the engine crashes into the house. You can see this sequence of events more clearly at the end of the film.
The Frank that Donnie speaks to throughout the movie is a Messenger sent to warn Donnie of the impending end of the world. The characters that are killed in the alternate universe are manipulated by whomever is helping Donnie save the world. They are known as Manipulated Dead and are briefly explained in the book from the director's cut.
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