A method of detecting variants in a target region of a sample genome of an organism, the method comprising: - receiving a plurality of sequence reads, the sequence reads obtained from sequencing genomic segments in a sample obtained from the organism, wherein the sequencing includes amplifying and/or enriching genomic segments from the target region; - identifying one or more alternate regions in a reference genome that have a respective first number of variations from the target region of a reference genome, each respective first number being greater than one and less than a first threshold number; - performing, with a computer system, an alignment of the plurality of sequence reads to the target region of the reference genome to identify a set of sequence reads that align to the target region of the reference genome with less than a second threshold number of variations; - removing from the set at least one sequence read that aligns to one or more of the alternate regions with a second number of variations that is less than a third threshold number; and - analyzing the remaining sequence reads of the set to determine variants in the target region of the sample genome, wherein identifying an alternate region includes: - counting a number of sequence reads that each differ from the target region of the reference genome at a same plurality of locations, the sequence reads having the same variations relative to the target region forming an alternate group; - if the number exceeds a cutoff value, performing an alignment of a first sequence read from the alternate group to the reference genome; and - if the alignment of the first sequence read to a first region of the reference genome has fewer variations than the alignment to the target region, identifying the first region as an alternate region. - receiving a plurality of sequence reads, the sequence reads obtained from sequencing genomic segments in a sample obtained from the organism, wherein the sequencing includes amplifying and/or enriching genomic segments from the target region; - identifying one or more alternate regions in a reference genome that have a respective first number of variations from the target region of a reference genome, each respective first number being greater than one and less than a first threshold number; - performing, with a computer system, an alignment of the plurality of sequence reads to the target region of the reference genome to identify a set of sequence reads that align to the target region of the reference genome with less than a second threshold number of variations; - removing from the set at least one sequence read that aligns to one or more of the alternate regions with a second number of variations that is less than a third threshold number; and - analyzing the remaining sequence reads of the set to determine variants in the target region of the sample genome, - counting a number of sequence reads that each differ from the target region of the reference genome at a same plurality of locations, the sequence reads having the same variations relative to the target region forming an alternate group; - if the number exceeds a cutoff value, performing an alignment of a first sequence read from the alternate group to the reference genome; and - if the alignment of the first sequence read to a first region of the reference genome has fewer variations than the alignment to the target region, identifying the first region as an alternate region.