acmg calculator

What is an ACMG calculator?

An ACMG calculator helps apply the ACMG/AMP framework for genetic variant interpretation in a consistent way. Instead of manually checking every rule combination, you can enter counts of evidence strengths (like PVS, PS, PM, PP, BA, BS, and BP) and quickly see the likely classification outcome: Pathogenic, Likely Pathogenic, VUS (Variant of Uncertain Significance), Likely Benign, or Benign.

This does not replace clinical judgment. It supports structured reasoning so your interpretation process is more transparent and reproducible.

Evidence strength categories at a glance

Category	Direction	Examples
PVS (Very Strong)	Pathogenic	PVS1 for predicted loss-of-function variants in genes where LoF is a known disease mechanism.
PS (Strong)	Pathogenic	Functional studies, established amino acid changes, de novo data (context dependent).
PM (Moderate)	Pathogenic	Low population frequency, hotspot/domain evidence, trans with pathogenic variant for recessive disorders.
PP (Supporting)	Pathogenic	Co-segregation, computational support, phenotype specificity.
BA (Stand-alone)	Benign	Allele frequency clearly incompatible with disease prevalence/penetrance.
BS (Strong)	Benign	Well-established benign functional evidence, high frequency in controls.
BP (Supporting)	Benign	Computational benign predictions, lack of segregation, benign observations.

How this calculator determines classification

Pathogenic and likely pathogenic logic

This page applies commonly used ACMG/AMP-style combination rules. For example, a variant can be called Pathogenic with combinations such as:

• 1 Very Strong + (1 Strong, or 2 Moderate, or 1 Moderate + 1 Supporting, or 2 Supporting)
• 2 or more Strong criteria
• 1 Strong + 3 Moderate (or other equivalent strong combinations)

Likely Pathogenic is assigned for combinations like 1 Very Strong + 1 Moderate, or 1 Strong + 1–2 Moderate, or 3 Moderate, among others.

Benign and likely benign logic

• Benign: BA alone, or at least 2 Strong benign criteria.
• Likely Benign: 1 Strong benign + 1 Supporting benign, or at least 2 Supporting benign criteria.

If both pathogenic and benign directions are triggered at the same time, the result is returned as VUS (conflicting evidence).

How to use this ACMG calculator well

1. Collect evidence from trusted sources (population databases, functional studies, segregation reports, phenotype data, curated resources).
2. Assign evidence strengths carefully. Do not double-count the same line of evidence.
3. Enter category counts into the calculator.
4. Review the triggered rules and confirm they match your interpretation notes.
5. Document assumptions, disease mechanism context, and any expert panel specifications used.

Common pitfalls to avoid

• Overweighting computational predictions: in most workflows these are supporting, not standalone proof.
• Ignoring phenotype mismatch: molecular evidence must be clinically coherent.
• Mixing disease mechanisms: a criterion may not apply the same way across genes or inheritance models.
• Forgetting population substructure: allele frequency interpretation depends on ancestry and database quality.

Practical examples

Example 1: Likely pathogenic

If you enter PVS=1, PM=1, and no benign evidence, this usually maps to Likely Pathogenic.

Example 2: Benign

Entering BA=1 (with anything else zero) returns Benign because stand-alone benign evidence is decisive in the ACMG framework.

Example 3: Conflicting evidence

Suppose you have PS=1 and PM=2 (pathogenic direction), but also BS=2 (benign direction). The model reports VUS due to conflicting evidence, prompting deeper review.

Final note

This ACMG calculator is designed for quick triage and teaching, not final sign-out. For clinical reporting, align with laboratory SOPs, ACMG/AMP updates, and disease-specific expert panel recommendations (for example, ClinGen VCEP modifications). Combine this output with variant-level evidence curation and multidisciplinary review.