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<i>Listeria monocytogenes</i> is a widespread foodborne pathogen of high concern and internalin A is an important virulence factor that mediates cell invasion upon the interaction with the host protein E-cadherin. Nonsense mutations of internalin A are known to reduce virulence. Although missense mutations are largely overlooked, they need to be investigated in respect to their effects in cell invasion processes. This work presented a computational workflow to early characterize internalin A missense mutations. The method reliably estimated the effects of a set of engineered missense mutations in terms of their effects on internalin A&#8722;E-cadherin interaction. Then, the effects of mutations of an internalin A variant from a <i>L. monocytogenes</i> isolate were calculated. Mutations showed impairing effects on complex stability providing a mechanistic explanation of the low cells invasion capacity previously observed. Overall, our results provided a rational approach to explain the effects of internalin A missense mutations. Moreover, our findings highlighted that the strength of interaction may not directly relate to the cell invasion capacity reflecting the non-exclusive role of internalin A in determining the virulence of <i>L. monocytogenes</i>. The workflow could be extended to other virulence factors providing a promising platform to support a better molecular understanding of <i>L. monocytogenes</i> epidemiology.