Mutational spectrum
Most (likely) pathogenic CYFIP2 variants reported to date are missense variants and typically occur de novo. Mutational hotspots are located at p.Arg87 and p.Asp724. Most reported variants clustered at protein-interaction interfaces in a structural model of the WAVE-regulatory complex. Further variants reported as disease-causing are an in-frame deletion and a variant affecting the canonical splice-site of the last intron.
Importantly, there is currently no clear evidence supporting pathogenicity or benignity of loss-of-function variants in CYFIP2.
Genotype-phenotype correlation
Individuals with a pathogenic variant at the hotspot p.Arg87 show a consistently severe phenotype of developmental and epileptic encephalopathy. For other variants, no clear genotype-phenotype correlation has been established.
CYFIP2