About Mutations



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A genetic association indicates a correlation between a phenotype and a DNA variant. Within this database, associations between a variant and disease are reported based on the study investigators’ criteria for statistical significance, generally p < 0.05. In instances where investigators set a different threshold for statistical significance, that threshold is noted.

Domain Mapping of Disease Mutations

Domain mapping of disease mutations refers to an approach in which knowledge of disease-causing variants in one protein is used to infer pathogenicity of variants at homologous positions in related proteins.

Incomplete Penetrance

Penetrance refers to the extent to which individuals carrying a particular variant also develop the disease. Some variants appear to be fully penetrant, i.e., all known carriers develop disease. Other variants are partially penetrant, i.e., one or more carriers do not develop disease. Incomplete penetrance may result from a combination of genetic, environmental, and lifestyle factors.

Linkage Disequilibrium

Linkage disequilibrium is the nonrandom association of alleles at different loci. It usually occurs because the alleles are near each other and inherited together on the same chromosome.

Nucleotide Change

Nucleotide change denotes the common reference nucleotide and the variant nucleotide at a given position, e.g., A>G. Note that the APP and TREM2 genes are on the reverse strand of Chromosomes 21 and 6, respectively. Therefore, Alzforum shows the nucleotide change on the reverse strand, in order to match the codon change.


PolyPhen-2 (Polymorphism Phenotyping v2) is a tool that predicts the effect of an amino acid substitution on the structure and function of a human protein. PolyPhen-2 scores range from zero (tolerated) to 1 (deleterious). Note that SIFT and PolyPhen scores run in opposite directions.

Reference Assembly

A reference assembly is a reference genome sequence for a particular species. It is generated by piecing together sequences of DNA fragments, first into contigs, then scaffolds, and sometimes into entire chromosomes. The resulting collection of sequences is called a genome assembly. This database uses GRCh37 as the reference genome assembly.


Segregation refers to the co-occurrence of a suspected disease-causing variant and a disease phenotype. For diseases with an autosomal-dominant pattern of inheritance, the variant will be found in affected, but not in unaffected, individuals. For diseases with an autosomal-recessive pattern of inheritance, affected individuals will be homozygous for the variant, while unaffected individuals may lack the variant or be heterozygous for the variant.


SIFT (Sorting Intolerant from Tolerant) is an algorithm that predicts whether an amino acid substitution will affect protein function. SIFT scores range from zero (deleterious) to 1 (benign). Note that SIFT and PolyPhen-2 scores run in opposite directions.