2 obvious ones come to mind

(1) that there is a through fare for A-C via B that is higher than the components A-B plus B-C
(2) that there is married segment availability issues. e.g. there may be O class available when booking A-B and also from B-C - however when trying to book A-C via B , there is no O class available

The lower price may show up on a multi city search , however when you go to purchase you may well find that it reprices to the higher price or just errors out