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Almost everything I read before I did my rub rail (flexible vinyl with insert) said to use 5200. After removing the old rail and cleaning off old sealant, I filled the holes with 5200 as recommended. I was able to let it set and fully cure as the kit I purchased was short screws and end caps so I had to wait anyway. I'm glad I waited, it all set up rock solid so there was no worry about overlapping an old hole. A bead of 5200 was put down on the screw line, and the new rail was drilled and screwed. I put some 5200 in each screw hole before setting as well, maybe overkill with the bead already down but I feel as if you can't be too careful considering the sealant/adhesive/setting benefits gained from the 5200. Just clean it up good before it starts to set or you'll wind up living with it wherever it messed. If you're that worried about possibly doing this again, use 4200 for the bead all the way around that the rail will sit on. I don't see where any old 5200 remaining would be a major hindrance in a future replacement of a new identical replacement.

Do not try to use the old holes. Aside from it being impossible to line up, they may be a bit too big to reset screws in. The new holes will fasten more snugly and be exactly where you need them. I've seen new rub rail installed right after the old holes were filled with 5200 as well, but I'd think you'd wind up with a screw or three that overlaps an old hole and doesn't set perfectly.