Background <p>The <i>SLC9A6</i> gene encodes a monovalent sodium-selective sodium/hydrogen exchanger that is essential in regulating endosomal PH and volume. <i>SLC9A6</i> variants are associated with Christianson Syndrome, a severe neurodevelopmental disorder that is accompanied by seizures. It is unknown whether <i>SLC9A6</i> variants are associated with milder phenotypes.</p> Method <p>Trio-based whole-exome sequencing was performed in unrelated cases (families) with epilepsy without acquired causes. Previously reported <i>SLC9A6</i> variants were reviewed to analyze the mechanism underlying phenotype variations.</p> Results <p>Five hemizygous variants, including three null and two missense variants, were identified in five males. All the variants were absent in the gnomAD-all populations and the missense variants were predicted to be damaging by multiple in silico tools. The three patients with null variants presented with refractory epilepsies and severe developmental delay; one patient with missense variant in the transmembrane region showed refractory epilepsies and speech delay; and one patient harboring missense variant located in the loop region achieved seizure-free with favorable outcome. Further analysis revealed that the proportions of brain atrophy, microcephaly, and movement disorders in patients with missense variants were significantly lower than that of patients with null variants, suggesting a genotype-phenotype correlation. Additionally, previously reported missense variants in the pore/transmembrane region led to Christianson Syndrome, whereas variants outside these regions were associated with milder phenotype, suggesting a sub-regional effect.</p> Conclusion <p>Missense variants in <i>SLC9A6</i> are associated with mild partial epilepsies. The genotype-phenotype correlation and molecular sub-regional effect of <i>SLC9A6</i> help in explaining the mechanisms underlying phenotypic variations.</p>