Maynooth - Conor Murray's failure to play any rugby so far this season saw the scrumhalf omitted from the 42-man squad named by Ireland head coach Joe Schmidt for the November Tests on Wednesday.
The 29-year-old Munster star, who has formed one of the most formidable half-back partnerships in Test rugby with flyhalf Johnny Sexton, has been on the sidelines with a neck injury but is hopeful of playing again next month.
Murray's absence leaves a large gap to be filled with Kieran Marmion the most experienced of three scrumhalves with 22 caps - Luke McGrath and John Cooney have just eight between them.
Although Schmidt will be without Murray, the 111-times capped hooker and captain Rory Best returns after missing the tour of Australia.
The Six Nations Grand Slam champions, who also edged Australia 2-1 in their summer Test series, have four matches in November starting with an encounter against Italy in Chicago on Saturday week.
They then face Argentina in Dublin on November 10 before the visit of world champions New Zealand a week later, and round off the Tests against the United States on November 24.
Schmidt has given hope to three uncapped backs - Will Addison, Sam Arnold and Ross Byrne - to stake their claims to be in next year's World Cup squad.
"As always there have been a number of close calls in selection, meaning that some very good players have missed out in this particular window," Schmidt said in an Irish Rugby Football Union (IRFU) statement.
"The upcoming series offers an exciting opportunity for the squad but will also be very challenging."
Addison is rewarded for some eye-catching performances in the Ulster midfield since his signing in the summer from English Premiership side Sale Sharks, while Arnold has impressed with Munster since his arrival from Ulster.
Leinster flyhalf Byrne has experienced being part of the national squad, as he went on the tour of Australia but did not play.
Schmidt has recalled Ulster centre Stuart McCloskey and Munster's Darren Sweetnam, while Rob Herring is one of four hookers despite being out injured in recent weeks.
Forwards (24): Rory Best (Ulster, capt), Finlay Bealham (Connacht), Tadhg Beirne (Munster), Jack Conan (Leinster), Sean Cronin (Leinster), Tadhg Furlong (Leinster), Cian Healy (Leinster), Iain Henderson (Ulster) Rob Herring (Ulster), Dave Kilcoyne (Munster), Dan Leavy (Leinster), Jack McGrath (Leinster), Jordi Murphy (Ulster), Sean O'Brien (Leinster), Peter O'Mahony (Munster), Andrew Porter (Leinster) Quinn Roux (Connacht), Rhys Ruddock (Leinster) James Ryan (Leinster), John Ryan (Munster), Niall Scannell (Munster), CJ Stander (Munster), Devin Toner (Leinster), Josh van der Flier (Leinster)
Backs (18): Will Addison (Ulster), Bundee Aki (Connacht), Sam Arnold (Munster), Ross Byrne (Leinster), Joey Carbery (Munster), Andrew Conway (Munster), John Cooney (Ulster), Keith Earls (Munster), Robbie Henshaw (Leinster), Rob Kearney (Leinster), Jordan Larmour (Leinster), Kieran Marmion (Connacht), Stuart McCloskey (Ulster), Luke McGrath (Leinster), Garry Ringrose (Leinster), Jonathan Sexton (Leinster), Jacob Stockdale (Ulster), Darren Sweetnam (Munster)
Ireland v Italy (Soldier Field, Chicago, Nov 3)
Ireland v Argentina (Lansdowne Road, Dublin, Nov 10)
Ireland v New Zealand (Lansdowne Road, Nov 17)
Ireland v United States (Lansdowne Road Nov 24)