Despite the increasing health risk from infantile cataracts, identifying the mechanism of this disease remains a challenge due to a lack of structural investigations using experimental and computational approaches. Mutations in human gamma S-crystallin are contingent with childhood cataracts. Our recent high-resolution structural studies using solution NMR spectroscopy established the key role of the G57W mutation in human gamma S-crystallin (abbreviated hereafter as gamma S-G57W), promoting structural instability. In order to design therapeutics to delay or upset congenital cataracts, the characterization of the precursors to gamma S-G57W aggregation is indispensable. In this endeavor, we present microsecond long unbiased atomistic molecular dynamics simulations and principal component analyses that unfold insights into lens crystallin aggregation. An enhanced sampling metadynamics approach was further employed to systematically unravel the molecular dynamics underlying crucial interdomain contacts. Taken together, our experiment-guided computational study in this paper led to the identification of domain-swapped intermediates in gamma S-G57W to atomic resolution with insights into the aggregation of lens crystallins causing childhood cataracts for the first time with functional consequences.