Closing base pairs affect the stability of 2×2 CC/CC internal loops formed by r(C4G2) exp . In ALS/FTD, foci are composed of both sense r(G4C2) exp and antisense r(C4G2) exp RNAs , which can be targeted by small molecules for therapeutic uses. The antisense r(C4G2) exp is a C-rich RNA sequence, which forms 2×2 CC/CC internal loops. At low pH, C-rich RNA sequences can form a four-stranded structure named RNA i-motif, which are not stable at physiological conditions . On the other hand, it is suggested that C-rich sequences would form excess non-Watson-Crick C/C base pairs . In an attempt to provide structural information, the antisense RNA structure of the C9orf72 has been studied by X-ray crystallography, which displayed each C/C mismatch to form a single hydrogen bond in 2×2 CC/CC loops . This pattern of hydrogen bonding has been already observed in 1×1 C/C internal loops . The overall RNA structure was classified as A-form although multiple deviations from a typical A-form RNA was reported.