Documentation / Variant Analysis / Criteria Reference
ACMG/AMP Criteria Reference
This page summarizes the clinical meaning and current execution status of each ACMG/AMP criterion. Exact application depends on variant type, disease mechanism, inheritance, source quality, applicable ClinGen guidance, and the evidence available for the case.
Status labels
Automated means the production pipeline can evaluate the criterion from governed data. Clinical review means the evidence depends on case-level judgment or information not inferred by the pipeline. Governed means an implementation exists but activation depends on validated reference data and deployment configuration.
Pathogenic Evidence
Predicted loss of function where loss of function is an established disease mechanism
Same amino acid change as an established pathogenic variant
De novo occurrence with confirmed parental relationships
Well-established functional evidence supports a damaging effect
Increased prevalence in affected individuals
Location in a critical functional region without benign variation
Absent or sufficiently rare in population reference data
Observed in trans with a pathogenic partner in a recessive disorder
Protein length change in an applicable non-repeat context
Different pathogenic missense change at the same residue
Assumed de novo occurrence without confirmed parental relationships
Cosegregation with disease in affected family members
Missense change in a gene where missense variation is an established disease mechanism
Calibrated computational evidence supports a damaging effect
Patient phenotype is highly specific for the associated disorder or gene
A reputable clinical source reports pathogenicity
Benign Evidence
Population frequency is incompatible with the disorder
Population frequency is greater than expected for the disorder
Observed in healthy individuals where full penetrance is expected
Well-established functional evidence supports no damaging effect
Lack of segregation with disease
Missense change in a gene where truncating variation is the established mechanism
Allelic observation is inconsistent with the proposed disease mechanism
In-frame length change in a repetitive region without known function
Calibrated computational evidence supports no damaging effect
An alternate molecular basis explains the case
A reputable clinical source reports benignity
Synonymous change with no predicted splice impact
Framework boundary
This reference describes nuclear sequence-variant criteria. Mitochondrial and structural variants use dedicated specifications that include, exclude, or modify criteria for their biology and evidence model.