HEXA rs28940578: Tay-Sachs Carrier Variant Explained
The rs28940578 variant in the HEXA gene is a 4-base pair insertion (commonly designated c.1278dupTATC or 1278insTATC) that leads to a frameshift and premature protein truncation. It is the single most common pathogenic variant associated with Tay-Sachs disease in individuals of Ashkenazi Jewish ancestry, accounting for over 70% of disease alleles in that population. Carrying one copy of this variant confers carrier status for autosomal recessive Tay-Sachs disease without causing clinical symptoms in the carrier.
What each genotype means
Typical HEXA enzyme activity
This genotype indicates the absence of the specific 4-bp insertion variant associated with Tay-Sachs disease at this location. Individuals with this result do not carry this specific pathogenic allele, though other rare variants in the HEXA gene could still exist.
This is the most common genotype observed across all global populations.
Tay-Sachs disease carrier
This genotype indicates you are a carrier of the c.1278dupTATC variant, which is a common cause of Tay-Sachs disease. Carriers typically do not develop the disease themselves, but you should discuss reproductive carrier screening and family planning with a genetic counselor or healthcare provider.
Carried by approximately 1 in 60 individuals of Ashkenazi Jewish descent, and is significantly less common in the general population.
Increased risk for Tay-Sachs
This genotype indicates the presence of two copies of the pathogenic insertion variant, which is associated with Tay-Sachs disease. Because this is an autosomal recessive condition, you should consult with a medical geneticist or specialist to discuss clinical implications and diagnostic testing.
This genotype is extremely rare, occurring at a frequency consistent with the incidence of Tay-Sachs disease in the population.
What is rs28940578 and Where is it Located?
The variant cataloged as rs28940578 is an insertion mutation within the HEXA gene, located on chromosome 15 at position 15q23. Clinically designated as c.1278dupTATC (or historically 1278insTATC), the variant involves a 4-base pair duplication of the sequence 'TATC' within exon 11. This insertion disrupts the reading frame of the transcript (p.Tyr427IlefsTer5), resulting in five altered amino acids followed by a premature termination codon. The truncated mRNA transcript is predominantly degraded by nonsense-mediated decay, preventing normal protein synthesis. When translated, the resulting protein fragment lacks the critical catalytic segments needed for enzymatic function. As a consequence, this mutation leads to an essentially complete loss of functional enzyme production from the affected allele, classifying it as a classic null mutation in clinical molecular genetics databases such as ClinVar.
The Biological Role of the HEXA Gene
The HEXA gene provides the genetic blueprint for the alpha subunit of the heterodimeric lysosomal enzyme beta-hexosaminidase A. In healthy cells, beta-hexosaminidase A pairs with a beta subunit (encoded by HEXB) and cooperates with the GM2 activator protein to break down GM2 ganglioside, a complex glycosphingolipid abundant in cell membranes of the central nervous system. Inside cellular lysosomes, this enzyme hydrolyzes GM2 ganglioside into GM3 ganglioside, allowing cellular lipids to be recycled. When both copies of the HEXA gene harbor severe loss-of-function variants like rs28940578, functional beta-hexosaminidase A activity drops to near zero. Without this enzyme, GM2 gangliosides progressively accumulate within neuronal lysosomes, causing swelling, cellular dysfunction, and severe progressive neurodegeneration characteristic of Tay-Sachs disease.
Associated Health Conditions and Clinical Evidence
Decades of peer-reviewed literature and curated database records in ClinVar classify rs28940578 as a well-established pathogenic variant for autosomal recessive Tay-Sachs disease (also known as infantile GM2 gangliosidosis). In an autosomal recessive inheritance model, an individual must inherit two disease-causing alleles—one from each biological parent—to be clinically affected. Biallelic inheritance of rs28940578, or compound heterozygosity with another severe HEXA null variant, leads to the classic infantile form of Tay-Sachs disease. Symptoms typically manifest between 3 and 6 months of age, involving developmental regression, loss of motor skills, an exaggerated startle response, seizures, and progressive neurological impairment. Individuals who inherit only one copy of rs28940578 are asymptomatic carriers who retain adequate hexosaminidase A enzyme activity from their functional allele.
Population Frequency and Historical Context
The rs28940578 variant exhibits pronounced allele frequency differences across global ancestry groups due to historical founder effects and genetic drift. In the Genome Aggregation Database (gnomAD), the allele frequency of rs28940578 in individuals of Ashkenazi Jewish ancestry is approximately 0.016, translating to a carrier frequency of roughly 1 in 30 individuals. In contrast, the carrier rate in the general non-Jewish population is estimated between 1 in 250 and 1 in 300, with rs28940578 appearing extremely rarely outside specific founder cohorts. Historically, rs28940578 accounts for more than 70% to 80% of all Tay-Sachs disease alleles identified in Ashkenazi Jewish populations. Targeted carrier screening programs established since the 1970s have utilized this variant on standard panels, dramatically reducing the live-birth incidence of classic infantile Tay-Sachs disease.
Navigating Carrier Status and Reproductive Planning
Identifying the rs28940578 variant on a direct-to-consumer genetic panel or carrier screen indicates carrier status, not a personal illness. Carriers are healthy and do not develop Tay-Sachs disease or neurological decline. However, the information has direct relevance for reproductive planning. If both prospective biological parents carry a pathogenic HEXA variant, there is a 25% chance in each pregnancy of having an affected child, a 50% chance of having a child who is also an unaffected carrier, and a 25% chance of having a non-carrier child. Direct-to-consumer array genotyping may not sequence the entire HEXA gene or measure biochemical enzyme levels. Therefore, individuals who identify as carriers or who have a family history of Tay-Sachs should seek confirmatory testing through an accredited clinical laboratory and consult a certified genetic counselor.
How common is this variant?
The rs28940578 variant is enriched in Ashkenazi Jewish populations with an allele frequency of approximately 0.016 (~1 in 30 individuals are carriers), whereas it is extremely rare in the broader global population, where carrier frequency is roughly 1 in 250 to 1 in 300.
Frequently asked questions
Does having the HEXA rs28940578 variant mean I have Tay-Sachs disease?
No. Carrying one copy of the rs28940578 variant simply means you are an unaffected carrier. Tay-Sachs disease is an autosomal recessive condition, meaning clinical disease only occurs if an individual inherits two non-functional copies of the HEXA gene.
Can carriers of the rs28940578 variant experience late-onset symptoms?
Heterozygous carriers of rs28940578 do not develop late-onset neurological symptoms or mild forms of Tay-Sachs disease. Their single normal copy of the HEXA gene produces sufficient hexosaminidase A enzyme to prevent toxic GM2 ganglioside accumulation in nerve cells.
What steps should I take if I test positive as a carrier?
If you learn you carry rs28940578, discuss the finding with a genetic counselor or your healthcare provider to confirm the result with clinical-grade diagnostic testing. If you are planning a family, having your reproductive partner tested for HEXA mutations or enzyme activity will clarify your shared reproductive risks.
Why is rs28940578 more common in Ashkenazi Jewish individuals?
The elevated frequency of rs28940578 in the Ashkenazi Jewish population is attributed to historical population bottlenecks and genetic drift that occurred centuries ago. Because of this founder effect, specific ancestral variants expanded in frequency compared to the broader global population.
Sources & further reading
Educational information only, last refreshed 9/6/2026. Not medical advice — these associations describe population statistics, not individual predictions.
Curious what your genotype is for rs28940578?
Upload a raw DNA file from 23andMe, AncestryDNA, MyHeritage, or FamilyTreeDNA and see this variant — plus thousands more — interpreted in your full report.
Get my report — $29Related variants in HEXA
Canonical splice junction variant (c.1073+1G>A) causing Tay-Sachs disease.
Pathogenic splice donor variant (c.1421+1G>C) in HEXA underlying carrier status for autosomal recessive infantile Tay-Sachs disease.
Pathogenic splice-junction variant (c.1073+1G>A / IVS9+1G>A) causing Tay-Sachs disease when in compound heterozygosity or homozygosity.
This HEXA variant is associated with Tay-Sachs disease, particularly late-onset forms.
Pathogenic splice junction mutation (c.1421+1G>C) in HEXA leading to Tay-Sachs disease.
Pathogenic HEXA splice donor site mutation (c.1073+1G>A) causing Tay-Sachs disease, common in carrier screening panels for Ashkenazi Jewish and French Canadian ancestry.