DNA strand morphing into a medical chart, symbolizing evolving gene classifications.

Decoding Gene Validity: How Clinical Classifications Evolve

Lena Kashyap in Health & Wellness December 2025 • 4 min read.

"A Deep Dive into ClinGen's Gene-Disease Assessments."

In the realm of precision medicine, understanding the link between genes and diseases is paramount. The Clinical Genome Resource (ClinGen) plays a crucial role in this by evaluating and classifying the clinical validity of gene-disease associations. This classification guides clinicians and researchers in interpreting genetic test results and tailoring treatments.

ClinGen employs a systematic framework where experts assess available evidence to categorize gene-disease associations as Definitive, Strong, Moderate, Limited, No Reported Evidence, or Conflicting Evidence Reported. These classifications are not static; new research and data can shift the understanding and, therefore, the classification of a gene's role in a disease.

This article explores how ClinGen's gene-disease clinical validity classifications evolve over time. By understanding these shifts and the factors driving them, clinicians and researchers can better interpret genetic information and ensure their knowledge remains current.

The Timeline of Gene Validity: Understanding the Shifts

DNA strand morphing into a medical chart, symbolizing evolving gene classifications.

To understand how these classifications change, a retrospective analysis was performed on 30 previously classified genes. This involved simulating the curation process at one-year intervals, starting from the initial publication asserting a gene's role in a disease. The aim was to identify trends in classification changes and the factors influencing these changes.

Here are some key findings from the study:

'Moderate' is a Launchpad: Gene-disease associations tend to move relatively quickly from a 'Moderate' classification to a 'Strong' or 'Definitive' one.
'Limited' Can Be a Long Road: Associations classified as 'Limited' for five or more years often remain in that category or are reclassified as 'Disputed/Refuted'.
Population Data Matters: Large population datasets, like ExAC and gnomAD, can significantly contribute to reclassifying gene-disease associations, particularly from 'Limited' to 'Disputed/Refuted' when common variants are identified in healthy individuals.
Technology Accelerates Discovery: Advances in sequencing technology, such as next-generation sequencing (NGS), correlate with an increased amount of case-level evidence being generated and curated.

These insights offer valuable guidance on how frequently gene-disease associations should be reevaluated to ensure accuracy and relevance.

Staying Ahead: Reevaluating for Precision Medicine

This research underscores the dynamic nature of gene-disease associations and the importance of continuous evaluation. A 'Limited' classification requires careful consideration, particularly if it persists over several years. Factors such as the availability of large population datasets and advancements in sequencing technologies play a crucial role in shaping these classifications.

Specifically, associations classified as 'Limited' for extended periods with low initial scores require less frequent reevaluation, focusing instead on monitoring for data that might dispute the association. Conversely, 'Moderate' associations and newly discovered 'Limited' associations warrant more frequent review.

By adopting a risk-based approach to reevaluation, ClinGen and other diagnostic testing providers can ensure that gene-disease classifications remain accurate and up-to-date, ultimately contributing to more informed clinical decision-making and improved patient outcomes.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1002/humu.23604, Alternate LINK

Title: The Progression Of The Clingen Gene Clinical Validity Classification Over Time

Subject: Genetics (clinical)

Journal: Human Mutation

Publisher: Wiley

Authors: Jennifer L. Mcglaughon, Jennifer L. Goldstein, Courtney Thaxton, Sarah E. Hemphill, Jonathan S. Berg

Published: 2018-10-11

Everything You Need To Know

What role does the Clinical Genome Resource (ClinGen) play in understanding the relationship between genes and diseases?

The Clinical Genome Resource, or ClinGen, systematically evaluates the evidence linking specific genes to particular diseases. It then classifies these gene-disease associations into categories such as Definitive, Strong, Moderate, Limited, No Reported Evidence, or Conflicting Evidence Reported, based on the strength and quality of the supporting data. These classifications provide clinicians and researchers with a standardized way to interpret genetic test results.

What does it mean if a gene-disease association receives a 'Moderate' classification from ClinGen, and what typically happens next?

When a gene-disease association is initially classified as 'Moderate' by ClinGen, it indicates that there is some evidence supporting the link, but more data is needed. The analysis indicates gene-disease associations tend to move relatively quickly from a 'Moderate' classification to a 'Strong' or 'Definitive' one as more evidence accumulates and is curated.

What are the implications if a gene-disease association remains classified as 'Limited' for an extended period, according to ClinGen's classification system?

If a gene-disease association remains classified as 'Limited' by ClinGen for five or more years, it often means that the evidence supporting the link is weak or inconclusive. In many instances, these associations either remain in the 'Limited' category or are reclassified as 'Disputed/Refuted' as more data becomes available.

How do large population datasets like ExAC and gnomAD influence ClinGen's classification of gene-disease associations?

Large population datasets, such as ExAC and gnomAD, play a crucial role in reclassifying gene-disease associations within the ClinGen framework. If common genetic variants, previously thought to be disease-causing, are found in healthy individuals within these datasets, the gene-disease association is more likely to be reclassified from 'Limited' to 'Disputed/Refuted'. This is because the presence of the variant in healthy individuals weakens the evidence supporting its role in causing the disease.

How have advances in sequencing technology, such as next-generation sequencing (NGS), affected how gene-disease associations are classified by ClinGen?

Advances in sequencing technology, particularly next-generation sequencing or NGS, have significantly impacted gene-disease classifications by generating more case-level evidence. NGS allows for the rapid and cost-effective sequencing of entire genomes, leading to the identification of more genetic variants in both affected and unaffected individuals. This increase in data accelerates the curation process and can lead to faster reclassification of gene-disease associations within ClinGen.