The Football Association of Wales has revealed an unspecified injury will sidelined the Sunderland midfielder at Hampden Park, though he will rejoin the squad ahead of Tuesday's game against Croatia.
Vaughan has played in his country's last two Group A fixtures, a 2-1 victory over Scotland at the Cardiff City Stadium on 12 October, followed by a 2-0 defeat away to Croatia four days later.
The FAW tweeted better news on Gareth Bale, confirming he should be fit for the Scotland game despite missing training on Wednesday with an ankle knock and an illness.
But Wales manager Chris Coleman will definitely be without Liverpool midfielder Joe Allen and Leeds striker Steve Morison.
Allen requires surgery to cure a shoulder problem and will be out for the rest of the season, while Morison has a calf problem.