Connections. Spectraplakins sit at the interface of architecture and motion inside a cell. They do not merely hold structures together but coordinate how the cytoskeleton rearranges itself when neurons migrate, polarize, and extend processes. One of the central spectraplakins is encoded by MACF1, a microtubule–actin crosslinking factor that couples microtubules to actin filaments and helps steer growing microtubules. This job requires multiple binding domains, flexibility, and scale. Spectraplakins are therefore large proteins encoded by enormous genes. A recent study examined how variants in MACF1 translate into human brain disease, and why seemingly similar variants may lead to surprisingly different neurodevelopmental outcomes. Here is why interpreting MACF1 variants is so complex.