The chromosomal ATPase Structural Maintenance of Chromatin flexible Hinge Domain containing 1 (Smchd1) is a protein essential for setting long-range chromatin interactions and the correct silencing of the inactive X chromosome, clustered autosomal genes and DUX4. This gene’s aberrant expression in muscle tissue is the cause of facioscapulohumeral muscular dystrophy type 2 (FSHD2). FSHD 2 patients have SMCHD1 loss-of-function mutations, while what where thought as gain-of-function mutations in the ATPase domain of SMCHD1 are associated with the craniofacial malformation Bosma Arhinia Microphthalmia Syndrome (BAMS). This has since become controversial as hypomethylation at the D4Z4 locus (which contains DUX4) has been reported both in FSHD-associated and BAMS-associated variants, and BAMS-associated variants show no increase in ATPase activity compared to wild type. A mutant version of Smchd1 found in an ENU screen showed promise as a gain-of-function candidate, with a single nucleotide mutation in the extended ATPase domain that caused it to change its structure. Further investigation has revealed a more complex picture, as this mutant has characteristics of both gain and loss-of-function depending on context. Transcriptionally, it tends to have the opposite effect to loss of Smchd1 in a cell type-dependent manner while its effects on chromatin structure as seen by HiC and ChIP for multiple histone marks indicates it is positively correlated to loss-of-function. Interestingly, data from collaborators in mouse myoblasts and mouse tissues seems to show that introducing this mutation reduces DUX4 expression. Though it is not a clear hyperactive version of Smchd1, this neomorphic mutation provides insight into the normal protein’s mechanism as well as a promising target for FSHD therapies.