TMTC2 (transmembrane O-mannosyltransferase targeting cadherins 2) is an endoplasmic reticulum-resident integral membrane protein that functions as an O-mannosyltransferase enzyme. TMTC2 transfers mannosyl residues from dolichyl-phosphate-mannose to serine or threonine residues on target proteins, with the four TMTC family members showing distinct roles in decorating cadherin domains with O-linked mannose glycans 1. The protein contains 11 transmembrane domains with tetratricopeptide repeat (TPR) domains oriented within the ER lumen, and structural modeling indicates it belongs to the GT-C/PMT superfamily of sugar transferases 1. Beyond its enzymatic function, TMTC2 serves as an adapter protein involved in ER calcium homeostasis, associating with SERCA2B calcium pump and calnexin chaperone 2. Clinically, TMTC2 variants are significantly associated with nonsyndromic sensorineural hearing loss, particularly the rs35725509 variant which causes progressive, bilateral hearing loss with characteristic audiometric patterns 3. Patients with TMTC2-associated hearing loss show favorable outcomes with cochlear implantation, achieving significant improvements in speech perception 4. TMTC2 has also been implicated in other conditions including glaucoma susceptibility, atopic march development, and as a potential biomarker in Parkinson's disease 567.