Which method for detection of rare variants in random human exome samples?

Hi, I am trying to detect rare variants that might only be present in one sample for rare diseases project. I have many exome samples of random population and I do not want to skip any rare variant. I am aware that multi-sample mode penalizes rare variants, and the same will happen if I use VQSR. For this specific case, should I do multi-sampling or single-sample mode?
Thank you very much

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