Definition
Variant of Uncertain Significance (VUS)
A variant of uncertain significance (VUS) is a genetic variant for which the available evidence is insufficient or conflicting, so it cannot be classified as pathogenic, likely pathogenic, likely benign or benign.
1 min readReviewed September 14, 2026
Also known as: Variant of unknown significance, Uncertain significance variant, VUS result
Key facts
- Tier position
- Middle tier of the five-tier ACMG/AMP scale
- ClinVar germline label
- Uncertain significance
- Optional ClinVar subcategories
- VUS-high, VUS-mid, VUS-low
What is a variant of uncertain significance?
A VUS is not a finding of disease and not a finding of no disease. It means the laboratory could not gather enough evidence to place the variant in any of the other four tiers of the scheme published by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP).
VUS results are common, especially with large gene panels and exome or genome sequencing, because the more of the genome a test examines, the more rare variants it finds that have never been studied.
How a VUS gets reclassified
A VUS can move to another tier when new evidence appears, for example:
- Population data showing the variant is too common to cause a rare disease.
- Functional laboratory studies showing whether the protein still works.
- Family studies showing whether the variant tracks with disease.
- Additional patients reported with the same variant and condition.
- Updated classification rules from expert panels.
Why VUS results matter
Published studies have found that most VUS later reclassified move to likely benign or benign rather than pathogenic. Because reference databases underrepresent many ancestral groups, people of non-European ancestry have historically received VUS results more often.
For analysts, VUS counts are a signal of evidence gaps in a gene. For diagnostic developers and laboratories, VUS rates and reclassification practices affect test design, reporting and follow-up workload. When counting variants in ClinVar, excluding or separating uncertain significance records avoids inflating estimates of disease-causing variants.
Common misconceptions about VUS results
A VUS is not a weaker form of a pathogenic result, and a VUS in ClinVar with conflicting classifications is not the same as a single laboratory VUS call. Practices for reanalyzing results and recontacting patients after reclassification vary between laboratories.