It is likely therefore that the effects of this substitution will be confined to the active site and have little or no effect on global protein stability or the ability to bind cyclin K. As such this variant might be expected to exhibit a strong dominant negative effect, and in fact the patient carrying this variant displayed one of the more severe phenotypes in our cohort, including growth restriction, microcephaly and moderate to severe ID. Here, CCNK is linked to microcephaly.