X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency characterised by an inability to produce immunoglobulins of the IgG, IgA and IgE isotypes. It is caused by mutations of CD40 ligand (CD40L, CD154), expressed on T-lymphocytes. The interaction of CD40L on T-cells and its receptor CD40 on B-cells is essential for lymphocyte signalling leading to immunoglobulin class switching and B-cell maturation. To understand the structural basis for XHIGM, we utilised bioinformatics methods to analyse all the known CD40L missense mutations at both the sequence and structural level. Our results demonstrate that the 35 different missense mutations have diverse effects on CD40L structure and function, affecting structural disorder and aggregation tendencies, stability maintaining contacts and electrostatic properties. Several mutations also affect residues essential in receptor binding and trimerisation. Experimental study of effects of mutations is laborious and time-consuming and at the structural level often almost impossible. By contrast, precise and useful information about effects of mutations on protein structure and function can readily be obtained by theoretical methods. In this study, all the XHIGM causing missense mutations could be explained in terms of CD40L structure and function. Thus, the molecular basis of the syndrome could be elucidated.