These CDRs show the largest degree of length and sequence variability. Particularly the CDR3 of the heavy chain shows a wide range of length variability as well as very large sequence variability.

Since CDR1 and CDR2 are determined by the V-Segment, their variability falls into a limited number of structural subsets. Analysis of these subsets has led to the definiton of so-called canonical residues indicative of the structure of CDR1 and CDR2. Since some of these residues are indicative of the V subtype present rather than causing the particular CDR conformation, the correlation often does not hold true for synthetic constructs obtained by grafting CDRs onto a different variable domain frameworks to obtain antibodies of a desired specificity with increased stability, better production yield and decreased antigenicity (humanization of antibodies)