We have implicated procadherin 19 - PCDH19, in girls clustering epilepsy (GCE) in 2008. In excess of 10 males with somatic mosaic PCDH19 mutation have also been reported. PCDH19 evolved to be the second most important epilepsy gene. We have developed a multidimensional pathogenicity assessment tool for PCDH19 using functional assays, in silico prediction and crystal structure modelling. We subsequently tested 25 variants; known disease-causing, VOUS as well as select, frequent population PCDH19 variants. Our systematic review of 300 published cases shows that the penetrance of PCDH19 GCE is about 70%, much less than >90% we estimated from family studies in 2008. The review also shows significant behavioural comorbidities (60%) and significant association between age at seizure onset and disease severity. No explanation for the variable penetrance between e.g., mothers and daughters or discordant MZ twins, have been identified. In this regard, we studied cellular and electrophysiological aspects of PCDH19 GCE using CRISPR/Cas9 modified mouse models with both, wt and KO PCDH19 alleles visualised. Only the heterozygous females showed altered brain EEG activity (altered SWDs). These mice also showed highly specific sorting and distribution of PCDH19 wt and PCDH19 KO neurons in their developing cortices (14.5dpc). Using patient-derived and iPSC models we show that gene expression (OXTR, APOD, etc.) and behaviour of the wt and KO cells differ significantly (in e.g. cell polarity and differentiation). We postulate that individually specific X-inactivation together with altered gene expression & functionality of wt and mutant PCDH19 cells are the underlying forces of PCDH19 GCE.