ASPA rs28934577: Understanding the p.Glu285Ala Variant
The rs28934577 variant in the ASPA gene is a pathogenic missense mutation known as p.Glu285Ala. It is strongly associated with Canavan disease, an inherited neurodegenerative disorder characterized by the accumulation of N-acetylaspartic acid in the brain.
What each genotype means
Typical ASPA function
This genotype represents the common, non-pathogenic sequence at this position in the ASPA gene. Individuals with this profile do not carry the specific Glu285Ala mutation associated with Canavan disease.
This is the most common genotype observed in the general population.
ASPA variant carrier
You carry one copy of the Glu285Ala variant, which is associated with Canavan disease. Because Canavan disease is an autosomal recessive condition, carrying a single copy typically does not cause symptoms, but you should consult with a genetic counselor regarding reproductive risks.
This genotype is carried by approximately 1 in 42 individuals of Ashkenazi Jewish ancestry, based on a reported allele frequency of 0.012.
Increased risk of Canavan disease
This genotype indicates the presence of two copies of the Glu285Ala variant. This variant causes aspartoacylase catalytic failure, which is the underlying cause of Canavan disease, a severe neurodegenerative leukodystrophy. Please discuss these results with a medical geneticist or healthcare provider for clinical evaluation.
This genotype is very rare in the general population, occurring primarily in individuals of Ashkenazi Jewish descent.
What is the rs28934577 Variant?
The rs28934577 variant, often referred to in clinical literature as p.Glu285Ala (or c.854A>C), is a specific change in the DNA sequence of the ASPA gene. This variant involves a single nucleotide substitution that results in the replacement of the amino acid glutamic acid with alanine at position 285 of the aspartoacylase protein. This change is classified as pathogenic because it significantly impairs the function of the enzyme. In the context of human genetics, this variant is recognized as a founder mutation, meaning it is found at a higher frequency in specific ancestral groups due to historical population dynamics. It is one of the primary genetic markers investigated when assessing the risk of Canavan disease, an autosomal recessive condition that affects the development and maintenance of the brain's white matter.
The Role of the ASPA Gene
The ASPA gene provides instructions for the body to produce an enzyme called aspartoacylase. This enzyme is primarily active in the brain, where it plays a critical role in the metabolism of N-acetylaspartic acid (NAA). Under normal conditions, aspartoacylase breaks down NAA into aspartate and acetate. This process is essential for the health of oligodendrocytes, the cells responsible for producing myelin—the protective sheath that insulates nerve fibers. When the ASPA gene contains pathogenic variants like rs28934577, the resulting enzyme is either absent or non-functional. This leads to an accumulation of NAA in the brain, which interferes with the normal structure and function of myelin. The resulting damage, known as spongy degeneration of the white matter, is the hallmark of Canavan disease, leading to progressive neurological symptoms.
Research and Clinical Significance
Research has firmly established the link between the p.Glu285Ala variant and Canavan disease. Studies indicate that this specific mutation results in an enzyme with only a tiny fraction—approximately 2.5%—of the activity found in the wild-type, healthy enzyme. Because Canavan disease is an autosomal recessive condition, an individual must typically inherit two copies of a pathogenic variant (one from each parent) to manifest the disease. The evidence for this variant's pathogenicity is strong, and it is widely included in carrier screening panels for individuals of Ashkenazi Jewish descent. While the association is well-documented, it is important to note that clinical presentation can vary. Genetic testing for this variant is used to identify carrier status, allowing families to make informed reproductive decisions with the guidance of genetic counselors.
Population Frequency
The rs28934577 variant is most frequently observed in the Ashkenazi Jewish population, where it is considered a founder mutation. Historical studies have estimated the carrier frequency for common ASPA mutations in this group to be approximately 1 in 40 to 1 in 60. Because of this relatively high carrier rate, screening programs have been established to identify carriers before pregnancy. Outside of the Ashkenazi Jewish population, the incidence of Canavan disease is significantly lower, estimated at 1 in 200,000 to 1 in 400,000. In non-Jewish populations, other mutations in the ASPA gene, such as p.Ala305Glu, are more commonly identified. The prevalence of rs28934577 remains highly specific to its ancestral context, highlighting the importance of considering ethnic background when interpreting genetic screening results.
Navigating Genetic Information
Understanding your carrier status for the rs28934577 variant is a personal health matter that should be handled with professional support. If you have received results indicating you are a carrier, it simply means you have one copy of the variant and are not expected to have the disease yourself. However, if both parents are carriers, there is a 25% chance for each pregnancy that the child will inherit two copies of the variant and potentially develop Canavan disease. This information is intended for educational purposes and should not be used for self-diagnosis. If you are concerned about your genetic risk or are planning a family, please consult with a board-certified genetic counselor or your primary care physician. They can provide context based on your specific family history and help you understand the implications of your genetic test results.
How common is this variant?
The rs28934577 variant is a founder mutation in the Ashkenazi Jewish population, with a carrier frequency estimated between 1 in 40 and 1 in 60.
Frequently asked questions
What is Canavan disease?
Canavan disease is a rare, inherited, and progressive neurodegenerative disorder. It is caused by a deficiency in the enzyme aspartoacylase, which leads to the buildup of N-acetylaspartic acid in the brain and the breakdown of myelin.
Does having the rs28934577 variant mean I have Canavan disease?
No. Canavan disease is an autosomal recessive condition, meaning it typically requires two copies of a pathogenic variant to manifest. Being a carrier (having one copy) does not cause the disease.
Should I get tested for this variant?
Carrier screening is often recommended for individuals of Ashkenazi Jewish descent who are planning a family. You should discuss the benefits and limitations of genetic testing with a healthcare provider or a genetic counselor.
Is there a cure for Canavan disease?
Currently, there is no cure for Canavan disease. Management focuses on supportive care to address symptoms, such as physical therapy for muscle tone and nutritional support.
Sources & further reading
Educational information only, last refreshed 10/15/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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Pathogenic founder mutation (p.Tyr231Ter) associated with Canavan disease.
Pathogenic missense variant (p.Glu285Ala / E285A) causing aspartoacylase deficiency and carrier status for autosomal recessive Canavan disease.
Common pathogenic nonsense mutation (p.Tyr231Ter) in ASPA underlying Canavan disease.
Severe pathogenic ASPA nonsense mutation (p.Tyr231Ter) responsible for Canavan disease in reproductive carrier screening.
Pathogenic ASPA missense variant (p.Glu285Ala) causing aspartoacylase deficiency (Canavan disease), standardly tested in preconception carrier panels.
A missense mutation (c.854A>C, p.Glu285Ala) in aspartoacylase causing Canavan disease in the homozygous state, representing one of the most common Jewish carrier screening alleles.