Human αB-crystallin discriminates between aggregation-prone and function-preserving variants of a client protein.

•The G18A variant of the eye lens protein γS-crystallin is less stable than wild-type.•γS-G18A causes minimal structural changes, unlike the cataract-related variant G18V.•The holdase chaperone protein αΒ-crystallin binds to γS-G18V but not γS-G18A.•αΒ-crystallin distinguishes aggregation-prone from soluble client protein variants.