Clark, who was on the fringes of the national team this time last year, is one of two uncapped players in the 33-man squad along with Gloucester centre Billy Twelvetrees.
Joe Launchbury, Tom Youngs, Mako Vunipola and Freddie Burns have all been formally promoted into the senior squad after impressing during England's autumn international campaign.
England's search for a left wing has led to a return for David Strettle in place of Charlie Sharples, who is more at home on the right, and James Haskell has replaced Phil Dowson in the back row.
Youngs has taken the place of injured Bath hooker Rob Webber, Launchbury has ousted Wasps team-mate Tom Palmer and Vunipola is an additional selection in an expanded 33-man squad.
Head coach Stuart Lancaster has dropped centres Anthony Allen and Jordan Turner-Hall for Burns and Twelvetrees. Clark has been preferred to Mouritz Botha.
The combative 23-year-old gives England options in both the back row and second row, offering the same versatility as his Northampton colleague Courtney Lawes.
Lancaster has been a long-time admirer of Clark's ability and he selected the Leeds academy graduate for last year's Six Nations squad. But Clark's career was put on hold in March, when he pleaded guilty to breaking the elbow of Leicester hooker Rob Hawkins in the LV= Cup final.
Twelvetrees has excelled in his first season at Gloucester, playing alongside Burns and both have been rewarded with their first formal call-ups.
The two playmakers trained with England during the autumn and Burns made an eye-catching debut off the bench in the 38-21 victory over New Zealand.
Calum Clark (Northampton Saints); Alex Corbisiero (London Irish); Dan Cole (Leicester Tigers); Tom Croft (Leicester Tigers); Dylan Hartley (Northampton Saints); James Haskell (London Wasps); Tom Johnson (Exeter Chiefs); Joe Launchbury (London Wasps); Courtney Lawes (Northampton Saints); Joe Marler (Harlequins); Ben Morgan (Gloucester Rugby); Geoff Parling (Leicester Tigers); Chris Robshaw (Harlequins); Mako Vunipola (Saracens); Thomas Waldrom (Leicester Tigers); David Wilson (Bath Rugby); Tom Wood (Northampton Saints); Tom Youngs (Leicester Tigers)
Chris Ashton (Saracens); Brad Barritt (Saracens); Mike Brown (Harlequins); Freddie Burns (Gloucester Rugby); Danny Care (Harlequins); Lee Dickson (Northampton Saints); Owen Farrell (Saracens); Toby Flood (Leicester Tigers); Ben Foden (Northampton Saints); Alex Goode (Saracens); Jonathan Joseph (London Irish); David Strettle (Saracens); Manusamoa Tuilagi (Leicester Tigers); Billy Twelvetrees (Gloucester Rugby); Ben Youngs (Leicester Tigers)