I feel for him (and you!)
DS2 has had very similar issues due to SEN and mild physical deformity too. They are draining to deal with and obviously, very upsetting for him.
First, I would just listen to him. I find it hard not to jumnp in with solutions or reassurances but I think they first need to be heard. If he is having a bad day, just say, 'You seem a bit low right now. Want to talk about it?' Or, ' You seem very down right now. What can I do to help?'
As a general note I introduced DS to 2 things that have really helped him. One is self care. I just started by saying - when you feel down, make sure you take very good care of yourself - nice baths, good comedy shows on TV and youtube, favourite food, favourite uplifting music in earphones etc. Maybe help him by looking for a cool new T shirt for him or suggesting a haircut.
The other thing is to expand your life so when one bit is really bad, some other bits support you. A way to do this is draw a square and divide it into 9 boxes then put an aspect of life in each bit of the grid - e.g. 1) Family 2) Health and fitness 3) Hobbies 4) Income etc. One of the boxes must be community or charity - the rest are whatever you like. Try to steer Friends and Romance lower down the grid so they are not the first ones he comes to. Get him to brainstorm some ideas of small, achievable goals he'd like to set for each aspect of life. Fitness is a great one to start with because everyone can do something about fitness - anything from increasing his number of pressups to a given number by the end of summer or learning weightlifting or kayaking etc. For the difficult ones like friends and romance, just help him set exploratory goals like joining a club or making some friends online.
He could also try setting up some online CBT sessions free on NHS if you are in England. I can send you a link if you are interested.
DS suffers from depression and due to his disabilities both physical and SEN, he has yet to find a girlfriend, but his life is so full now. He has loads of friends, goes on holiday with them, goes off to help at charities and has clubs and societies he belongs to. Life will never be as easy for him as it is for his tall, confident, conventionally good looking friends. He knows that and when you are young that is a painful thing to come to terms with. It gives me sleepless nights and I'm not the one living with it. But all you can do is improve the rest of life at every opportunity. He does that and I admire him enormously for it. First the friends came along and I am confident in time the girl and the job will come along too.