Mevalonate kinase (MVK) catalyses the phosphorylation of mevalonate. Deficiency of MVK is associated with two rare periodic fever syndromes, mevalonic aciduria (MA), a severe form and hyper‐immunoglobulin‐D syndrome (HIDS), a milder form. An in silico approach was used to analyse the physicochemical and structural effects of 47 disease‐associated variants of MVK. A further 20 variants, which are present in human genome databases, were also analysed. Variants associated with MA are clustered into a “hotspot” consisting of residues 8–35 and 234–338 and tended to result in a prediction of severely reduced protein stability. Four of the uncharacterised variants, p.H24P, p.G198R, p. R253W, and p.G335S, were likely to be associated with MA. This method could be used as the basis for initial predictions of severity when new MVK variants are discovered.