Most significant European river (4)
I believe the answer is:
main
I believe this clue is a double definition.
'most significant' is the first definition.
'european river' is the second definition.
(German river)
(Other definitions for main that I've seen before include "Chief; sea; pipe" , "Most important or greatest in size" , "Most important - high seas?" , "Source of water" , "associated with the Spanish?" .)