A computer implemented method for identifying disease-causing genetic variants within a feature, comprising: a) providing a genome variant file from at least one individual; b) annotating the variants, including annotation with respect to their impact on existing genome annotations, wherein the annotating is in respect to: - whether the variant is coding, non-coding, synonymous, non-synonymous, loss-of-function, stop codon causing, changes top regulatory elements, splice sites, or - known variant frequencies in a population; c) selecting a feature, wherein the feature comprises any span or collection of spans of a genome sequence or transcriptome sequence, and wherein the feature comprises a gene, a transcript, an exon, an intron, a UTR, a genetic locus, an extended gene region including regulatory elements, a list of 2 or more genes, a genetic pathway, an ontology category, or a combination thereof; and d) scoring the variants within the feature(s), wherein the scoring: i) compares composite allele frequencies in target genome(s) for the selected features in the genome variant file with the corresponding allele frequencies in a background database for selected features; ii) computes a statistical probability of each variant and as a composite in the selected feature; and iii) ranks variants and their corresponding features according to the statistical probability of each variant and/or of composite feature genotype(s); and wherein the scoring is based on calculating a composite likelihood ratio. a) providing a genome variant file from at least one individual; b) annotating the variants, including annotation with respect to their impact on existing genome annotations, wherein the annotating is in respect to: - whether the variant is coding, non-coding, synonymous, non-synonymous, loss-of-function, stop codon causing, changes top regulatory elements, splice sites, or - known variant frequencies in a population; - whether the variant is coding, non-coding, synonymous, non-synonymous, loss-of-function, stop codon causing, changes top regulatory elements, splice sites, or - known variant frequencies in a population; c) selecting a feature, wherein the feature comprises any span or collection of spans of a genome sequence or transcriptome sequence, and wherein the feature comprises a gene, a transcript, an exon, an intron, a UTR, a genetic locus, an extended gene region including regulatory elements, a list of 2 or more genes, a genetic pathway, an ontology category, or a combination thereof; and d) scoring the variants within the feature(s), wherein the scoring: i) compares composite allele frequencies in target genome(s) for the selected features in the genome variant file with the corresponding allele frequencies in a background database for selected features; ii) computes a statistical probability of each variant and as a composite in the selected feature; and iii) ranks variants and their corresponding features according to the statistical probability of each variant and/or of composite feature genotype(s); and wherein the scoring is based on calculating a composite likelihood ratio. i) compares composite allele frequencies in target genome(s) for the selected features in the genome variant file with the corresponding allele frequencies in a background database for selected features; ii) computes a statistical probability of each variant and as a composite in the selected feature; and iii) ranks variants and their corresponding features according to the statistical probability of each variant and/or of composite feature genotype(s);