ALD Grey Zone: Understanding an ABCD1 VUS

What does an ABCD1 VUS mean?

A variant is a difference in a DNA sequence. Not every variant causes disease. ABCD1 is the gene examined in ALD genetic testing. When a laboratory reports a variant of uncertain significance, or VUS, it means the available evidence is insufficient or conflicting about whether that change causes disease.

A VUS alone neither establishes nor excludes a diagnosis. Specialists interpret the result with blood testing, medical history, and family information. Sometimes more evidence can clarify the result; sometimes uncertainty remains.

Sources: MedlinePlus Genetics · International ALD recommendations.

Families may use “grey zone,” or “gray zone,” to describe living with unanswered questions. That phrase is not a diagnosis. A VUS is a specific laboratory classification; uncertainty about a person’s future can exist even when a variant has a different classification.

A variant’s classification and a child’s future are different questions

Does this variant cause disease?

Laboratories assess evidence and use terms such as benign, likely benign, uncertain significance, likely pathogenic, or pathogenic. Ask what evidence supports the wording on your report.

What will happen to this person?

Which symptoms may develop, when they might appear, and how severe they might be are different questions. An ALD-associated variant does not provide a reliable individual forecast.

“Likely pathogenic” does not mean “likely to develop a particular symptom at a particular age.” It describes evidence about the variant’s relationship to disease. Likewise, having no symptoms today does not settle every question about the future.

Sources: ACMG/AMP: variant interpretation standards · International ALD recommendations · MedlinePlus: interpreting results.

For questions about how a variant can be passed down or why relatives might be tested, see our ALD genetics and inheritance guide.

How does this fit with newborn screening?

An out-of-range newborn screening result flags the need for follow-up; it is not the same as a genetic diagnosis. Follow-up blood tests examine biochemical markers, while genetic testing looks at ABCD1. These results answer related but different questions.

Ask your specialists to explain what each test showed, how the findings fit together, and what remains unresolved. A VUS should not be interpreted in isolation. If your child has a monitoring plan, discuss new research with the team before making changes.

Sources: HRSA: newborn screening results and follow-up · International ALD recommendations.

Our newborn screening guide walks through follow-up, the different reports, and appointment preparation.

What is the Grey Zone Project?

The Grey Zone Project is an international research effort studying uncertain ABCD1 findings. ALD Connect describes confirmatory blood-marker testing intended to add information for families and clinicians dealing with uncertain variants.

The project’s name refers to a particular research effort, not every situation in which a family feels uncertain. If you are interested, ask your specialist whether it is relevant and contact the study team about current eligibility and participation. Do not assume that every uncertain result qualifies. Testing can add information, but it may not resolve every uncertain result or predict a person’s future. Discuss your results and care with your specialist.

Sources: ALD Connect: the Grey Zone Project.

What are the limits?

• Measurements came from one diagnostic laboratory. Its cutoffs should not be applied directly to results from another lab.
• A key comparison group was small: 27 older men who had myeloneuropathy but neither adrenal insufficiency nor cerebral ALD. They were not entirely unaffected.
• Many variants had few measurements. The authors call for larger, prospective validation—testing the approach in additional people followed over time.
• Childhood risk categories do not establish lifetime risk of every ALD manifestation.

The paper does not establish that an individual child can safely stop monitoring.

Sources: Read the full peer-reviewed paper.

Can a VUS classification change?

It can be reconsidered as evidence becomes available. Information from other people with the same variant, clinical findings, laboratory work, and family testing may help. A healthy older relative can be relevant information, but their experience is not a guarantee about another person’s future.

Ask who is responsible for requesting an updated interpretation: your genetics team, the testing laboratory, or another clinician. Do not assume that a database update will automatically reach you. Keep a copy of the original report, including the exact variant name, laboratory, and report date, so you can discuss any later changes clearly.

Sources: MedlinePlus: interpreting uncertain results · International ALD recommendations · Grey Zone Project paper.

Questions to bring to your specialists

You do not need to ask everything at once. Choose the questions that would make the next step clearer for your family.

Understanding the result

• What is confirmed, what is uncertain, and which test supports each conclusion?
• Is this still the laboratory’s current classification? Are there differing interpretations, and who can help explain them?
• Do the blood and genetic findings fit together? Does the type of sample, the laboratory method, or the age at testing affect how we interpret them?

Making a plan

• What monitoring do you recommend now, and what evidence would make you reconsider that plan?
• What should prompt a call between visits, and who should we contact?
• Would a genetic counselor or testing relatives help clarify our situation?
• Who will request an updated variant interpretation, and how will we hear about it?

Considering research

• Is the Grey Zone Project relevant to our family, and how do we confirm eligibility?
• What could research testing add, and what questions would it still leave unanswered?
• How would research findings be considered alongside our child’s clinical care?

A few terms you may hear

Biomarker

A measurable biological sign used as one piece of evidence. In this research, blood lipid measurements are biomarkers.

LPC(26:0), C26:0-LPC, or C26:0-lysoPC

Names used for the lipid marker studied by the Grey Zone Project. A marker measurement is not a scan of the brain or a genetic test.

Myeloneuropathy

Involvement of the spinal cord and peripheral nerves. Our adult ALD guide introduces this part of ALD.

Variant classification

A laboratory’s assessment of the evidence about whether a DNA change causes disease.

Prospective validation

Testing an approach in further participants followed over time to see how well it works.

Sources: Grey Zone Project paper · International ALD recommendations.

Sources and further reading

The sources below informed this guide. Independent ALD specialist review is pending.

• ACMG/AMP: variant interpretation standards · Genetics in Medicine, 2015; the five-category classification terminology.
• Lund, Kemp and colleagues: The Grey Zone Project · Journal of Inherited Metabolic Disease, first published February 9, 2026. DOI: 10.1002/jimd.70157.
• ALD Connect: the Grey Zone Project · Project information and current participation contacts.
• MedlinePlus Genetics: interpreting genetic test results · Uncertain findings and the limits of genetic predictions.
• Engelen and colleagues: international ALD recommendations · Neurology, 2022; expert consensus on diagnosis and management.
• HRSA: newborn screening results and follow-up · General screening results and next steps.