ASPA rs121907956: Understanding the p.Tyr231Ter Variant
The rs121907956 variant in the ASPA gene is a well-documented genetic change known as p.Tyr231Ter. It is recognized as a pathogenic founder mutation associated with Canavan disease, a rare inherited neurological disorder.
What each genotype means
Normal enzyme function
You carry two non-variant copies of the ASPA gene at this position and do not carry the p.Tyr231Ter mutation. Research indicates this genotype is associated with normal aspartoacylase enzyme production. It does not confer carrier status for Canavan disease via this specific founder variant.
Found in the vast majority of the general population worldwide, including over 98% of individuals of Ashkenazi Jewish ancestry.
Canavan disease carrier
You carry one copy of the p.Tyr231Ter (c.693C>A) nonsense variant in the ASPA gene, conferring carrier status for autosomal recessive Canavan disease. Carriers typically remain healthy and asymptomatic because one functional copy produces adequate enzyme activity. If planning a pregnancy, testing of reproductive partners and consultation with a genetic counselor is standard practice.
Observed in roughly 1 in 40 to 1 in 82 individuals of Ashkenazi Jewish descent, but extremely rare in other global ancestries.
Canavan disease risk
Carrying two copies of the p.Tyr231Ter variant results in a complete absence of functional aspartoacylase enzyme activity. In clinical literature, this homozygous genotype is causally associated with typical infantile Canavan disease, a severe progressive neurodegenerative leukodystrophy. Clinical evaluation and genetic counseling are recommended for full diagnostic context.
Extremely rare globally, estimated at approximately 1 in 6,400 births within the Ashkenazi Jewish population and far rarer in other ancestries.
What is the rs121907956 Variant?
The variant rs121907956, often referred to in scientific literature as c.693C>A or p.Tyr231Ter, is a specific change in the DNA sequence of the ASPA gene. This variant is classified as a nonsense mutation, meaning it introduces a premature stop signal during the process of protein synthesis. Instead of the cell producing a full-length, functional protein, the machinery stops reading the genetic code early. This results in the production of an abnormally short and nonfunctional version of the aspartoacylase enzyme. Because this variant is located within the coding region of the gene, it significantly disrupts the enzyme's ability to perform its normal biological tasks. It is widely studied in the context of clinical genetics due to its established role as a pathogenic variant, meaning it is known to cause disease when inherited in a specific pattern.
The Role of the ASPA Gene
The ASPA gene provides the essential 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 breakdown of a substance known as N-acetylaspartic acid (NAA). NAA is a compound found in high concentrations in the brain, and its proper regulation is vital for the maintenance of myelin, the protective sheath that covers nerve fibers and allows for efficient signal transmission. When the ASPA gene is mutated, as is the case with the p.Tyr231Ter variant, the resulting aspartoacylase deficiency leads to an accumulation of NAA in the brain. This buildup is toxic to the cells that produce myelin, leading to a process called spongy degeneration of the white matter. This disruption of myelin integrity is the underlying cause of the neurological symptoms associated with Canavan disease.
Research and Clinical Significance
Research has firmly established the link between the p.Tyr231Ter variant and Canavan disease. The condition follows an autosomal recessive inheritance pattern, meaning an individual must inherit two copies of a pathogenic variant—one from each parent—to manifest the disease. Carriers, who possess only one copy of the variant, typically do not exhibit symptoms of the condition. The evidence for this variant's pathogenicity is strong, as it has been consistently identified in individuals diagnosed with Canavan disease. While it is a major founder mutation in specific populations, it is important to note that over 80 different mutations in the ASPA gene have been identified globally. Clinical diagnosis of Canavan disease involves a combination of genetic testing to identify these specific variants and biochemical testing to measure elevated levels of NAA in urine or blood.
Population Frequency
The rs121907956 variant is notably prevalent in the Ashkenazi Jewish population, where it is considered a founder mutation. Historical studies and clinical data suggest that the carrier frequency for this specific variant, alongside others in the ASPA gene, is approximately 1 in 40 within this community. Because of this relatively high frequency, carrier screening programs have been established to help individuals understand their reproductive risks. While the variant is most frequently discussed in the context of Ashkenazi Jewish ancestry, Canavan disease is a global condition that can occur in any ethnic group. In non-Ashkenazi populations, the genetic landscape of the disease is more diverse, and the specific mutations responsible may differ. Consequently, genetic testing strategies are often tailored based on an individual's ancestry and clinical presentation.
What This Information Means for You
Understanding your genetic status regarding the rs121907956 variant is primarily relevant for reproductive planning and family health history. If you are identified as a carrier, it simply means you have one copy of the variant and do not 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 not a medical diagnosis and should not be used to predict personal health outcomes outside of the context of carrier status. If you have concerns about your genetic results or family history, it is essential to consult with a certified genetic counselor or a medical geneticist. These professionals can provide personalized guidance, explain the implications of your results, and discuss appropriate testing options for you and your family members.
How common is this variant?
The carrier frequency for this variant is approximately 1 in 40 in the Ashkenazi Jewish population, though estimates can vary between 1 in 40 and 1 in 82.
Frequently asked questions
What is Canavan disease?
Canavan disease is a rare, progressive, and fatal neurological disorder that affects brain development. It is caused by a deficiency of the enzyme aspartoacylase, leading to the accumulation of N-acetylaspartic acid in the brain.
Does being a carrier mean I have the disease?
No, being a carrier means you have one copy of the mutated gene but do not have the disease. Carriers are typically healthy and do not show symptoms of the condition.
How is Canavan disease inherited?
It is inherited in an autosomal recessive pattern. This means an affected individual must inherit two copies of the pathogenic variant, one from each parent.
Should I get tested for this variant?
Carrier screening is often recommended for individuals of Ashkenazi Jewish descent or those with a family history of Canavan disease. You should discuss the appropriateness of testing with a genetic counselor or your healthcare provider.
Sources & further reading
Educational information only, last refreshed 10/27/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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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.
A nonsense mutation (c.693C>A, p.Tyr231Ter) in ASPA leading to truncated aspartoacylase and defining carrier status for Canavan disease.