ASPA rs28940579: What Your Genotype Means
The genetic variant rs28940579 is a single nucleotide polymorphism located in the ASPA gene that creates a premature stop codon (p.Tyr231Ter). It is recognized as a major pathogenic founder mutation for Canavan disease, an autosomal recessive neurodegenerative disorder. Individuals carrying one copy of the variant are asymptomatic carriers who face no personal health impairment but may pass the allele to biological children.
What each genotype means
Negative for Canavan variant
You do not carry the c.693C>A (p.Tyr231Ter) pathogenic variant in the ASPA gene. Because Canavan disease is inherited in an autosomal recessive pattern, having two standard alleles means you are not at elevated risk for being a carrier of this specific founder mutation. However, this result does not rule out other rare pathogenic variants across the ASPA gene.
Found in more than 99% of most global populations, including over 98% of individuals of Ashkenazi Jewish ancestry.
Canavan disease carrier
You carry one copy of the c.693C>A nonsense variant in the ASPA gene, which classifies you as an asymptomatic carrier for Canavan disease. Carriers do not typically develop symptoms because one functioning copy of the gene is sufficient for normal enzyme activity. If planning a pregnancy, your reproductive partner can be offered carrier screening to evaluate the risk of having an affected child.
Carried by approximately 1 in 80 to 1 in 100 individuals of Ashkenazi Jewish ancestry, but extremely rare in general non-Ashkenazi populations.
Likely affected with Canavan disease
Carrying two copies of the c.693C>A (p.Tyr231Ter) variant introduces premature stop codons in both ASPA alleles, causing a severe deficiency of aspartoacylase enzyme activity. In clinical literature, this homozygous state is strongly associated with typical infantile-onset Canavan disease, a progressive leukodystrophy characterized by developmental delay, hypotonia, and macrocephaly. These genomic findings warrant detailed discussion with a medical geneticist or pediatric neurologist.
Extremely rare across all ancestral groups, occurring in fewer than 1 in 40,000 live births in Ashkenazi Jewish populations and virtually absent elsewhere.
Genetic Architecture of rs28940579
The single nucleotide variant rs28940579 is located on the short arm of chromosome 17 (17p13.2) within the ASPA gene. At the nucleotide level, this alteration corresponds to a cytosine-to-adenine substitution at coding position 693 (c.693C>A). In protein terms, this alteration substitutes a tyrosine residue at amino acid position 231 with a premature termination codon, annotated as p.Tyr231Ter or Y231X. Because it introduces an early stop signal, the resulting messenger RNA is typically subjected to nonsense-mediated decay, or it produces a severely truncated peptide that lacks normal catalytic function. This variant is classified as a loss-of-function allele, leading to a complete absence of functional protein output from the affected chromosomal copy.
Biological Role of the ASPA Gene
The ASPA gene provides instructions for producing the metabolic enzyme aspartoacylase. This enzyme plays a crucial biochemical role within the central nervous system by breaking down N-acetyl-L-aspartic acid (NAA) into aspartic acid and acetate. Aspartic acid serves as a fundamental building block for proteins and functions as a neurotransmitter, while acetate is an essential component required for the biosynthesis of fatty acids and the maintenance of the myelin sheath that insulates nerve fibers. When aspartoacylase is absent or nonfunctional due to biallelic ASPA disruption, NAA accumulates to toxic levels within the brain and is excreted heavily in urine. This metabolic buildup disrupts oligodendrocyte health, inhibits proper myelination, and causes the progressive white matter spongiform degeneration characteristic of Canavan disease.
Clinical Significance and Strength of Evidence
Clinical genetic databases such as ClinVar and comprehensive reviews like GeneReviews classify rs28940579 as a well-established pathogenic variant associated with typical, infantile-onset Canavan disease when present in the homozygous state or in trans with another pathogenic ASPA allele. Infantile Canavan disease is a severe, progressive leukodystrophy marked by developmental regression, macrocephaly, severe hypotonia, and early childhood mortality. Because Canavan disease follows an autosomal recessive inheritance pattern, heterozygous individuals carrying only one copy of rs28940579 are asymptomatic carriers. Carriers possess sufficient residual enzyme activity from their single functioning ASPA copy to prevent NAA accumulation and maintain normal neurological health. Evidence supporting the variant's role in Canavan disease is robust, validated by decades of clinical observations and functional enzymatic analyses.
Population Frequency and Carrier Screening
The rs28940579 variant is one of two prominent founder mutations in the ASPA gene—alongside p.Glu285Ala—that account for the majority of Canavan disease alleles in individuals of Ashkenazi Jewish heritage. Within the Ashkenazi Jewish population, historical studies report an overall carrier frequency for Canavan disease of approximately 1 in 40 to 1 in 82, with rs28940579 representing a notable fraction of those carrier alleles (roughly 1 in 100 individuals). In contrast, the variant is exceptionally rare across non-Ashkenazi populations, where different ASPA variants such as p.Ala305Glu or deep structural insertions are more commonly identified. Professional organizations, including the American College of Medical Genetics and Genomics (ACMG), recommend pan-ethnic carrier screening for Canavan disease during pregnancy or preconception planning.
Interpreting Results and Clinical Next Steps
Understanding an rs28940579 genotype is primarily useful for reproductive planning rather than personal disease prognosis. Having one variant allele does not signify that an individual has Canavan disease or will develop neurological symptoms later in life. Instead, carrier status indicates an autosomal recessive inheritance risk: if two biological parents are both carriers of an ASPA pathogenic mutation, each pregnancy carries a 25% chance of inheriting both mutated copies and being affected by Canavan disease. Individuals with consumer DNA or clinical carrier results should not treat raw genotype files as an absolute diagnostic finding. Anyone identified as a carrier should consult a certified genetic counselor or physician to verify the finding in an accredited clinical laboratory and discuss partner screening or reproductive options.
How common is this variant?
The rs28940579 variant is largely concentrated in populations of Ashkenazi Jewish heritage, where its carrier frequency is approximately 1 in 100 (contributing to an overall Canavan carrier rate of 1 in 40 to 1 in 82). In non-Ashkenazi populations, this specific variant is extremely rare in broad population databases such as gnomAD.
Frequently asked questions
Does having the rs28940579 variant mean I have Canavan disease?
No, having a single copy of rs28940579 makes you an asymptomatic carrier. Canavan disease is an autosomal recessive condition, meaning an individual must inherit two nonworking copies of the ASPA gene to be affected. Carriers lead normal, healthy lives and do not show symptoms of the disease.
Why is rs28940579 more common in Ashkenazi Jewish populations?
The rs28940579 alteration represents a historical founder mutation that became enriched in the Ashkenazi Jewish population over generations due to population bottlenecks and genetic drift. While it is one of the most common ASPA mutations in this ancestry, other distinct ASPA variants cause Canavan disease in other global populations.
What steps should I take if my test reports I am a carrier?
If consumer or clinical testing identifies you as a carrier, the recommended step is to discuss the finding with a certified genetic counselor. A counselor can confirm the result using a clinical-grade diagnostic panel and evaluate carrier screening options for your reproductive partner.
Can Canavan disease be passed down if only one parent is a carrier?
If only one biological parent is a carrier of an ASPA mutation and the other parent has two functioning copies, a child cannot inherit the full condition. There is a 50% chance the child will also be an unaffected carrier and a 50% chance they will inherit two standard alleles.
Sources & further reading
Educational information only, last refreshed 9/12/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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