Immanuel Feyi-Waboso will miss England's Six Nations opener against Wales with a leg muscle injury.
Feyi-Waboso failed to complete a training session on Thursday and scrum coach Tom Harrison confirmed the explosive 23-year-old will sit out the Allianz Stadium showdown.
Tom Roebuck fills the vacancy on the right wing in what will be his first appearance since starting against New Zealand in November, with a toe problem keeping him sidelined since.
Feyi-Waboso is one of England's main attacking threats with his explosive carrying and electric footwork earning a comparison with cross-code great Jason Robinson from assistant coach Kevin Sinfield during the autumn.
"The only slight concern we have is Manny. He pulled up at the end of training, at the very end," defence coach Richard Wigglesworth said on Thursday.
The versatile and experienced Elliot Daly had been predicted to replace Feyi-Waboso but Roebuck will instead wear the No 14 jersey. Henry Arundell starts on the left wing.
England will be led into Saturday's Twickenham showdown by Jamie George, who deputises for Maro Itoje after the regular captain was named on the bench having missed some of the pre-tournament training camp in Girona to attend the funeral of his mother Florence.
George was skipper for 2024 when England won five of their 12 Tests - a sequence that included a string of narrow defeats, including three to New Zealand - and is delighted to take charge once again.
"Brilliant and unexpected. I didn't ever see that happening again after our tour to Argentina in the summer," said George, who will retire after the 2027 World Cup.
"It's a privilege. I love this job, it's the best thing in the world being able to do this. It's for one week and one week only so I'm making the most of it.
"Maro's the captain of this team. It's his team and he's doing an unbelievable job, so I feel responsibility, as you should, to make sure you get it right."
Crisis-hit Wales are outsiders to triumph at Twickenham but George reckons it is a "free swing" for Steve Tandy's side. He insists his team are embracing the expectation generated by winning 11 successive Tests.
"I've been around too long not to lean into being favourites. The elephant in the room - we've been in good form recently. We haven't shied away from it," George said.
England: 15 Freddie Steward, 14 Tom Roebuck, 13 Tommy Freeman, 12 Fraser Dingwall, 11 Henry Arundell, 10 George Ford, 9 Alex Mitchell; 1 Ellis Genge, 2 Jamie George (c), 3 Joe Heyes, 4 Alex Coles, 5 Ollie Chessum, 6 Guy Pepper, 7 Sam Underhill, 8 Ben Earl.
Replacements: 16 Luke Cowan-Dickie, 17 Bevan Rodd, 18 Trevor Davison, 19 Maro Itoje, 20 Tom Curry, 21 Henry Pollock, 22 Ben Spencer, 23 Marcus Smith.
