InterVar

open_source

InterVar is a free, open-source bioinformatics tool that interprets genetic variants using the 28 ACMG/AMP 2015 criteria, classifying them as Pathogenic, Likely Pathogenic, VUS, Likely Benign, or Benign.

Data & Analytics

Research & Education

AI Research Tools

About

InterVar is a bioinformatics software tool developed by the Wang Genomic Lab for standardized clinical interpretation of genetic sequence variants according to the ACMG/AMP 2015 guidelines. These guidelines define 28 evidence criteria split into pathogenic/likely pathogenic (P/LP) and benign/likely benign (B/LB) categories, ranging from very strong (PVS1) to supporting evidence levels (PP, BP). The tool operates in two major steps: first, it automatically evaluates variants against all applicable criteria; second, it allows users to manually adjust the evidence codes to refine the final clinical significance call. The web platform, wInterVar, provides a searchable pre-built database of over 100 million exonic variant sites updated through August 2025, supporting both hg19 and hg38 genome builds. Users can query variants by genomic coordinates, dbSNP IDs, HGNC gene symbols with cDNA changes, or protein-level changes. An API endpoint is available for programmatic or direct linking to specific variants. For local use with indels, the full InterVar tool is available on GitHub. Companion tools include CancerVar for somatic/cancer variant interpretation and CNVinter for germline copy number variation analysis. InterVar is widely used by clinical geneticists, molecular pathologists, bioinformaticians, and researchers aiming to reduce inter-interpreter variability when classifying genetic variants in both research and clinical diagnostic contexts.

Key Features

28-Criteria ACMG/AMP Classification: Automatically evaluates variants against all 28 pathogenic and benign evidence criteria defined in the ACMG/AMP 2015 guideline, from very strong to supporting evidence levels.
Two-Step Interpretation Workflow: Combines automated algorithmic classification with the ability for users to manually adjust evidence codes and re-interpret clinical significance.
Multiple Query Modes: Supports variant lookup by genomic coordinate, dbSNP ID, HGNC gene symbol with cDNA change, or protein change, across hg19 and hg38 genome builds.
Pre-Built Database of 100M+ Sites: Queries a continuously updated database of over 100 million exonic variant sites, last updated August 2025, for fast interpretation without local setup.
API Access: Provides a direct API endpoint for programmatic variant queries and linking, enabling integration into existing bioinformatics pipelines and workflows.

Use Cases

Clinical laboratories classifying germline exonic variants for diagnostic reporting using standardized ACMG/AMP 2015 criteria.
Research groups performing large-scale variant pathogenicity assessments across cohorts in population genomics studies.
Bioinformaticians integrating variant interpretation into automated annotation pipelines via the InterVar API.
Genetic counselors and molecular pathologists reviewing and manually adjusting automated variant classifications before issuing clinical reports.
Academic institutions using InterVar as a teaching tool to illustrate ACMG/AMP guideline-based variant classification workflows.

Pros

Standardized, Guideline-Based Classification: Implements the widely adopted ACMG/AMP 2015 framework, reducing inter-interpreter variability and ensuring reproducible variant classification.
Free and Open-Source: Available as both a free web tool and a downloadable open-source package on GitHub, making it accessible to academic and clinical labs alike.
Regularly Updated Databases: The wInterVar pre-built databases are updated periodically (most recently August 2025), ensuring variant annotations reflect current knowledge.
Ecosystem of Companion Tools: Integrates with CancerVar for somatic variants and CNVinter for CNVs, offering a suite of specialized variant interpretation tools.

Cons

Exon Variants Only (Web Version): The wInterVar web interface supports exonic variants only; users with indels, intronic, or other variant types must download and run InterVar locally.
Germline Variants Only: Cancer/somatic variants and CNVs are not supported within InterVar itself and require separate companion tools (CancerVar, CNVinter).
Requires ANNOVAR Annotation for Local Use: The local/command-line version requires input to be pre-annotated using ANNOVAR, adding a dependency and setup step for new users.

Frequently Asked Questions

The ACMG/AMP 2015 guideline is a set of standards published by the American College of Medical Genetics and Genomics for classifying sequence variants into five categories: Pathogenic, Likely Pathogenic, Uncertain Significance, Likely Benign, and Benign, using 28 defined evidence criteria.

No. InterVar is designed for germline exonic variants. For cancer or somatic variant interpretation, use the companion tool CancerVar. For germline copy number variants (CNVs), use CNVinter.

InterVar provides a direct 'Interpret by Criteria' option on the web interface, allowing you to input your known evidence codes and receive the classification without re-querying the database.

The wInterVar web tool supports both hg19 and hg38 genome builds, with pre-built databases available for multiple versions including the latest 2025 updates.

Yes. InterVar offers an API endpoint for direct linking to specific variants, enabling programmatic access and integration into automated bioinformatics workflows.