The Leinster fly-half has been struggling with a thumb issue and has been left out of Joe Schmidt's team for the match at Twickenham.
With Joey Carbery absent due to an ankle problem, Ross Byrne will make his first Test start and hope to stake his claim for World Cup selection.
Schmidt has made 12 changes from the team that beat Italy 29-10 on August 10, with Rory Best returning to captain the side and Cian Healy joining him in the front row for his 90th cap.
Peter O'Mahony, CJ Stander and Josh van der Flier team up in the back row, while Conor Murray, Jacob Stockdale, Bundee Aki and Rob Kearney return in the backs.
Ireland XV: Rob Kearney, Jordan Larmour, Garry Ringrose, Bundee Aki, Jacob Stockdale, Ross Byrne, Conor Murray; Cian Healy, Rory Best, Tadhg Furlong, Iain Henderson, Jean Kleyn, Peter O'Mahony, Josh van der Flier, CJ Stander.
Replacements: Sean Cronin, Jack McGrath, Andrew Porter, Devin Toner, Tadhg Beirne, Luke McGrath, Jack Carty, Andrew Conway.