A case of Costello syndrome with a hotspot HRAS substitution p.Gly12Ser and an in silico analysis of the correlation between genotype and clinical severity

Abstract Costello syndrome (CS) is a rare RASopathy caused by germline-activating variants in HRAS . We report a Japanese boy with CS harboring the hotspot substitution c.34G>A p.(Gly12Ser) and assess whether computational pathogenicity prediction (AlphaMissense) aligns with clinical severity scores. The patient developed arrhythmia at 1 month and showed marked motor and speech delays. At the age of 7 years, he presented with characteristic curly hair, deep palmar and plantar creases, and pronounced hyperkeratosis on the hands and feet. To examine genotype–phenotype correlations, we reviewed 14 HRAS missense variants reported in 10 publications, retrieved AlphaMissense scores, and quantified clinical severity using the McCormick scoring system. For each variant, the mean severity was compared with predicted pathogenicity using Spearman’s correlation. Variants affecting p.Gly12 visually appeared to be associated with higher clinical severity than non-p.Gly12 variants did, highlighting the functional importance of this residue. However, no significant correlation was observed between AlphaMissense and clinical severity (ρ = 0.126, P = 0.667), likely reflecting the limitations of current scoring systems that focus on systemic complications while overlooking dermatologic and neurodevelopmental features. Our findings highlight the need for an expanded, clinically meaningful CS severity scale integrating dermatologic and neurodevelopmental dimensions to better capture genotype–phenotype relationships and guide personalized management.