PLEKHB1 (pleckstrin homology domain containing B1) is a membrane-associated protein with roles in cellular signaling and neurological function. The gene encodes a brain-specific pleckstrin homology domain-containing protein with established function in primary sensory neurons 1. PLEKHB1 is involved in receptor and signal transduction processes 2 and participates in multiple cellular pathways including calcium signaling, cGMP-PKG signaling, endocytosis, and Rap1 signaling 3. Regarding disease relevance, PLEKHB1 has been implicated in several pathological conditions. The gene shows differential expression patterns in brain tumors, being upregulated in gliomas driven by PDGF 4 and differentially expressed between pilocytic astrocytoma and glioblastoma 2. In neurodegenerative disease, PLEKHB1 mRNA and protein levels are deregulated in motor neurons at disease onset in TDP-43-driven amyotrophic lateral sclerosis models, suggesting functional importance in the transition to symptomatic disease 5. Additionally, PLEKHB1 harbors autosomal-recessive biallelic variants associated with cloacal exstrophy 6 and contains copy number variations linked to attention-deficit/hyperactivity disorder 1. From a clinical perspective, PLEKHB1 variants are associated with elite strength athlete phenotypes as part of a polygenic profile 7.