Johnny Sexton has been ruled out of Ireland's RBS 6 Nations opener against Scotland after failing to shake off his calf problem.
Ireland must now face Scotland at Murrayfield on Saturday without their linchpin British and Irish Lions playmaker.
Ulster's Paddy Jackson should now start at fly-half in Edinburgh, with Munster's Ian Keatley drafted into the squad as extra cover.
Flanker Peter O'Mahony will also miss the Scotland clash after suffering a hamstring problem, in another blow to head coach Joe Schmidt's side.
Uncapped Munster centre Rory Scannell is Ireland's only other recognised option at fly-half, after Schmidt chose to overlook Bordeaux's Ian Madigan.
The Irish Rugby Football Union (IRFU) confirmed the sizeable injury blow by tweeting: "Johnny Sexton has done some running but will not be considered for selection for this weekend.
"Johnny did some light running but is still feeling some tightness. He will continue to rehab but won't be selected this weekend."
Sexton suffered his latest injury blow in Leinster's 24-24 European Champions Cup draw at Castres on January 20.
The 31-year-old limped out of the first half of Leinster's draw in France, detecting the calf issue himself with his provincial bosses hoping a quick withdrawal would boost his chances of being fit to start the Six Nations.
Ireland had expected Sexton to return to full training on Tuesday, and had banked on the 63-cap playmaker winning his fitness battle to face the Scots.
Now Ulster's 25-year-old Jackson will step up into Ireland's number 10 shirt, having run the backline operations throughout training last week.
Schmidt has already defended his decision to overlook former Leinster fly-half Madigan for selection.
The IRFU favour those playing club rugby in Ireland for Test selection, with Schmidt happy to follow that trend.
While 19-cap Jackson has the experience to cope with the starting jersey, Keatley boasts just four caps - and has not featured since Ireland's 26-3 win in Italy in February 2015.
Why are you making commenting on The Herald only available to subscribers?
It should have been a safe space for informed debate, somewhere for readers to discuss issues around the biggest stories of the day, but all too often the below the line comments on most websites have become bogged down by off-topic discussions and abuse.
heraldscotland.com is tackling this problem by allowing only subscribers to comment.
We are doing this to improve the experience for our loyal readers and we believe it will reduce the ability of trolls and troublemakers, who occasionally find their way onto our site, to abuse our journalists and readers. We also hope it will help the comments section fulfil its promise as a part of Scotland's conversation with itself.
We are lucky at The Herald. We are read by an informed, educated readership who can add their knowledge and insights to our stories.
That is invaluable.
We are making the subscriber-only change to support our valued readers, who tell us they don't want the site cluttered up with irrelevant comments, untruths and abuse.
In the past, the journalist’s job was to collect and distribute information to the audience. Technology means that readers can shape a discussion. We look forward to hearing from you on heraldscotland.com
Comments & Moderation
Readers’ comments: You are personally liable for the content of any comments you upload to this website, so please act responsibly. We do not pre-moderate or monitor readers’ comments appearing on our websites, but we do post-moderate in response to complaints we receive or otherwise when a potential problem comes to our attention. You can make a complaint by using the ‘report this post’ link . We may then apply our discretion under the user terms to amend or delete comments.
Post moderation is undertaken full-time 9am-6pm on weekdays, and on a part-time basis outwith those hours.
Read the rules here