Putting an official answer on here for anyone else that is having issues with this. If I used dc on the signatures field and then modified the where clause to be total_signatures, it worked perfectly for me. I still have all of the variables that I need for adaptive response.
index=security*sep sourcetype IN (symantec:ep:proactive:file, symantec:ep:risk:file) | stats count by dest, signature, file_name, file_path, file_hash | stats dc(signature) AS total_signatures, values(file_name) as process, values(file_path) AS full_path, values(file_hash) AS sha256 count by dest | where total_signatures > 1
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