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Background: The von Hippel-Lindau disease is an autosomal dominant syndrome associated with tumour formation in various tissues, such as retina, central nervous system, kidney, and adrenal glands. VHL gene deletion or mutations support the development of various cancers. Unclassified VHL variants also referred as "of unknown significance" result from gene mutations that have an unknown or unclear effect on protein functions. The P81S mutation has been linked to low penetrance Type 1 disease but its pathogenic function was not clearly determined., Methods: We established a stable cell line expressing the pVHL 213 (c.241C>T, P81S) mutant. Using biochemical and physiological approaches, we herein analysed pVHL folding, stability and function in the context of this VHL single missense mutation., Results: The P81S mutation mostly affects the non-canonical function of the pVHL protein. The cells expressing the pVHL 213 P81S acquire invasive properties in relation with modified architecture network., Conclusion: We demonstrated the pathogenic role of this mutation in tumour development in vhl patients and confirm a medical follow up of family carrying the c.241C>T, P81S., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)