A computer-implemented method of detecting low frequency variants in a target region in a first sample, the method comprising, at a computer system: - receiving a plurality of sequence reads obtained from sequencing DNA fragments from one or more samples, the one or more samples including the first sample, wherein the sequencing includes targeting the target region in the DNA fragments; - aligning the plurality of sequence reads to the target region of a reference sequence; - identifying a first candidate variant having a first variant allele at a first location of the target region based on sequence reads of the first sample differing from a reference allele at the first location of the reference sequence; - determining a first variant frequency for the first variant allele at the first location based on sequence reads of the first sample that align to the first location of the reference sequence, the reference allele including one or more bases; - identifying a set of second locations in the target region of the reference sequence that has the one or more bases of the reference allele, wherein the set of second locations includes the first location; at each location of the set of second locations and for each of the one or more samples: - determining a second variant frequency of the first variant allele based on sequence reads of the sample that align to each location of the set of second locations of the reference sequence, the second variant frequencies forming a statistical distribution; - comparing the first variant frequency to a statistical value of the statistical distribution to determine a probability value indicating a confidence level that the first variant allele is a true positive at the first location, wherein the statistical value corresponds to a mean or a central position of the statistical distribution; and - comparing the probability value to a threshold value as part of determining whether the first candidate variant is a true positive in the first sample for the first variant allele at the first location, the threshold value differentiating between false positives and true positives for the first variant allele, wherein the threshold value is determined using a support vector machines classifier based on training data with known true positives and false positives. - receiving a plurality of sequence reads obtained from sequencing DNA fragments from one or more samples, the one or more samples including the first sample, wherein the sequencing includes targeting the target region in the DNA fragments; - aligning the plurality of sequence reads to the target region of a reference sequence; - identifying a first candidate variant having a first variant allele at a first location of the target region based on sequence reads of the first sample differing from a reference allele at the first location of the reference sequence; - determining a first variant frequency for the first variant allele at the first location based on sequence reads of the first sample that align to the first location of the reference sequence, the reference allele including one or more bases; - identifying a set of second locations in the target region of the reference sequence that has the one or more bases of the reference allele, wherein the set of second locations includes the first location; - determining a second variant frequency of the first variant allele based on sequence reads of the sample that align to each location of the set of second locations of the reference sequence, the second variant frequencies forming a statistical distribution; - comparing the first variant frequency to a statistical value of the statistical distribution to determine a probability value indicating a confidence level that the first variant allele is a true positive at the first location, wherein the statistical value corresponds to a mean or a central position of the statistical distribution; and - comparing the probability value to a threshold value as part of determining whether the first candidate variant is a true positive in the first sample for the first variant allele at the first location, the threshold value differentiating between false positives and true positives for the first variant allele,