SIX6 rs33912345: What Your Genotype Means
The rs33912345 variant is a common genetic change in the SIX6 gene that alters a single amino acid in the resulting protein. Research indicates this variant is associated with variations in retinal nerve fiber layer thickness and may influence the risk of developing primary open-angle glaucoma.
What each genotype means
Typical retinal structure
This genotype represents the non-risk version of the SIX6 variant. Research indicates that individuals with this profile generally exhibit thicker retinal nerve fiber layers compared to those carrying the C allele, which is associated with glaucoma risk.
The frequency of this genotype varies significantly by ancestry, being more common in populations of European descent compared to African or East Asian populations.
Intermediate retinal profile
Carrying one copy of the C allele is associated with a measurable, dose-dependent reduction in retinal nerve fiber layer thickness. While this is a known risk factor for primary open-angle glaucoma, it does not guarantee the development of the condition.
This heterozygous genotype is found at varying frequencies globally, reflecting the underlying prevalence of the C allele in different ancestral groups.
Increased glaucoma risk profile
This genotype is associated with a significantly thinner retinal nerve fiber layer and a higher statistical risk for primary open-angle glaucoma. Research suggests this variant may affect optic nerve development and maintenance, though these effects are often more pronounced in older age groups.
The C allele is highly prevalent in many populations, with the homozygous CC genotype being very common in some East Asian and African cohorts.
Understanding the rs33912345 Variant
The rs33912345 variant is a single nucleotide polymorphism (SNP) located within the SIX6 gene. Specifically, this variant results in a missense mutation where the amino acid asparagine is replaced by histidine at position 141 (Asn141His). Because this change occurs within the homeobox region of the SIX6 protein—a critical area for DNA binding—it is hypothesized to affect the protein's ability to regulate gene expression during development. Scientists have identified this variant as a common genetic marker in studies investigating ocular health, particularly in relation to the structure of the optic nerve and the retina. It is often studied alongside other variants in the SIX1/SIX6 locus, as these genes are located close together on the chromosome and are frequently inherited together in blocks known as linkage disequilibrium.
The Role of the SIX6 Gene
The SIX6 gene provides instructions for creating a transcription factor, which is a protein that helps turn other genes on or off. This process is essential for the proper development of the eye, particularly the retina and the optic nerve. During early development, SIX6 helps regulate the proliferation and differentiation of retinal progenitor cells, ensuring that the eye structures form correctly. Because of its role in shaping the neural retina, researchers have long suspected that variations in this gene could contribute to structural differences in the eye. When the SIX6 protein function is altered, it may lead to subtle changes in the thickness of the retinal nerve fiber layer (RNFL). These structural variations are of significant interest to ophthalmologists because the thinning of the RNFL is a hallmark feature observed in conditions like primary open-angle glaucoma.
Research and Statistical Associations
Multiple studies have demonstrated a statistical association between the rs33912345 variant and ocular measurements. Research has shown that individuals carrying the risk allele (C) often exhibit a thinner retinal nerve fiber layer, particularly in the superior and inferior sectors of the eye. These findings have been replicated across various populations, including European and Asian cohorts. While the association with glaucoma risk is statistically significant, it is important to note that this variant is not a diagnostic tool. Many individuals with the risk allele do not develop glaucoma, and many without it do. The evidence suggests that the variant acts as a susceptibility factor, potentially influencing the eye's structural resilience over time. Some studies indicate that these effects may be age-dependent, becoming more pronounced as individuals grow older, which highlights the complex interplay between genetics and the aging process in ocular health.
What This Information Means for You
If you have information about your rs33912345 genotype, it is important to view it as a single piece of a much larger biological puzzle. Genetic associations are statistical probabilities observed in large groups of people and cannot predict an individual's health outcome. Having a specific genotype does not mean you will develop a disease, nor does it guarantee protection from one. This information should never be used to self-diagnose or make medical decisions. If you are concerned about your eye health, particularly regarding glaucoma or retinal changes, the most effective step is to schedule a comprehensive eye examination with an optometrist or ophthalmologist. They can perform clinical tests, such as optical coherence tomography (OCT) or visual field testing, which provide direct, actionable data about your eye health that genetic testing alone cannot offer.
How common is this variant?
The frequency of the C risk allele varies significantly by ancestry, being very common in some populations and less frequent in others, such as those of European descent.
Frequently asked questions
Does having the rs33912345 risk allele mean I will get glaucoma?
No. This variant is a susceptibility factor, meaning it is statistically associated with a higher risk, but it is not a direct cause of glaucoma. Many factors, including eye pressure, age, and family history, play a much larger role in your actual risk.
Should I get my eyes checked if I have the C/C genotype?
Everyone should have regular eye exams regardless of their genetic profile. If you are concerned about your risk, share your family history and any genetic information with your eye doctor, who can determine the appropriate screening schedule for you.
Is rs33912345 the only gene involved in glaucoma?
No, glaucoma is a complex, polygenic condition involving many different genes and environmental factors. The SIX6 variant is just one of many genetic markers that researchers have identified as being associated with the disease.
Can I change my genotype?
No, your genotype is determined at conception and cannot be changed. However, understanding your genetic predispositions can help you and your healthcare provider focus on proactive health monitoring.
Sources & further reading
Educational information only, last refreshed 11/1/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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A missense coding variant associated with optic nerve thinning and primary open-angle glaucoma susceptibility.
Common variant in the SIX1-SIX6 locus associated with vertical cup-to-disc ratio and primary open-angle glaucoma (POAG) risk.
Coding variant in SIX6; associated with retinal nerve fiber layer thickness and glaucoma susceptibility.