CYP1B1 rs121912646: What Your Genotype Means
The rs121912646 variant in the CYP1B1 gene is a well-documented genetic change associated with primary congenital glaucoma. This missense mutation, often referred to as p.Gly61Glu, affects the stability and function of the CYP1B1 enzyme, which plays a critical role in eye development.
What each genotype means
Typical thyroid hormone synthesis
You carry two reference copies of the TG gene at this position and do not carry the nonsense variant associated with congenital thyroid dyshormonogenesis. Published research indicates that individuals with this genotype produce standard thyroglobulin from this locus, assuming no other pathogenic variants are present across the gene. This genotype confers standard baseline population risk for inherited thyroid dyshormonogenesis.
Carried by more than 99.9% of individuals across global populations in gnomAD, representing the overwhelming majority genotype.
Carrier of thyroid dyshormonogenesis
You carry one copy of the premature stop codon variant (p.Arg1530* / p.Arg1511*) in the TG gene. Because thyroid dyshormonogenesis type 3 follows an autosomal recessive inheritance model, heterozygous carriers typically maintain normal thyroid hormone levels and do not develop congenital hypothyroidism on their own. If planning a pregnancy, carrier status may be clinically relevant if reproductive partners are also carriers of pathogenic TG variants.
Carried by fewer than 1 in 5,000 individuals worldwide, with gnomAD reporting an alternate allele frequency of approximately 0.00007 to 0.00009.
Elevated dyshormonogenesis risk
You carry two copies of the loss-of-function stop codon alteration in the TG gene. In published medical literature and ClinVar assertions, homozygous or compound heterozygous disruption of thyroglobulin leads to primary congenital hypothyroidism caused by impaired thyroid hormone biosynthesis (thyroid dyshormonogenesis type 3). Individuals with biallelic null alleles typically present in infancy with low thyroid hormone production and elevated thyroid-stimulating hormone requiring clinical evaluation.
Extremely rare in the general population, observed in fewer than 1 in 1,000,000 individuals and primarily documented in consanguineous pedigrees.
Understanding the Variant
The variant rs121912646, also known as c.182G>A or p.Gly61Glu, is a single nucleotide change located within the CYP1B1 gene. In this specific mutation, the amino acid glycine is replaced by glutamic acid at position 61 of the protein sequence. This change is classified as a missense variant, meaning it alters the genetic code to produce a protein with a different amino acid than the original. Because glycine is neutral and non-polar, while glutamic acid is acidic and polar, this substitution can significantly impact the protein's structure. Research indicates that this specific alteration leads to a substantial loss of protein stability, which in turn reduces the overall abundance and functional capacity of the enzyme within the body's cells.
The Role of the CYP1B1 Gene
The CYP1B1 gene provides instructions for making an enzyme called cytochrome P450 1B1. This enzyme is part of the cytochrome P450 family, which is primarily involved in breaking down various substances in the body, including certain hormones and toxins. Beyond its metabolic roles, CYP1B1 is essential for the normal development of the eye, particularly the structures involved in the drainage of aqueous humor, the fluid that maintains pressure inside the eye. When the CYP1B1 enzyme is absent or functions poorly due to genetic mutations, the drainage system of the eye may not develop correctly. This can lead to an accumulation of fluid, resulting in increased intraocular pressure, a hallmark of primary congenital glaucoma. The enzyme's role in maintaining redox homeostasis and regulating developmental pathways makes it a critical component of ocular health.
Research and Clinical Associations
Scientific research has established a strong link between the p.Gly61Glu variant and primary congenital glaucoma, an autosomal recessive condition. Studies have shown that individuals carrying this mutation often require more surgical interventions to manage intraocular pressure compared to those with other forms of glaucoma. The evidence for its pathogenicity is supported by functional studies demonstrating that the mutated protein loses approximately 60% of its stability compared to the wild-type version. While this variant is a major cause of congenital glaucoma in specific populations, it is important to note that the clinical presentation can be variable. Some individuals may show significant differences in severity between their two eyes. Because this is a complex genetic condition, clinical diagnosis and management should always be handled by ophthalmologists and genetic counselors who can interpret these findings in the context of a patient's full clinical history.
Population Frequency
The frequency of the rs121912646 variant varies significantly across different ancestral groups. It is notably more common in populations of Saudi Arabian and Moroccan ancestry, where it has been identified as a frequent cause of primary congenital glaucoma. In broader, outbred cohorts, the allele frequency is quite low, typically estimated at approximately 0.0005 or 0.05%. Because the condition is inherited in an autosomal recessive manner, an individual generally needs to inherit two copies of a pathogenic variant—one from each parent—to be at high risk for the disease. The presence of this variant in population databases, including instances of homozygous individuals, underscores its role as a known, albeit rare, genetic factor in global populations.
What This Information Means for You
If you or a family member have been identified as a carrier of the rs121912646 variant, it is essential to understand that this information is for educational purposes and does not constitute a medical diagnosis. Genetic testing results should always be discussed with a qualified healthcare provider or a genetic counselor who can provide context based on your family history and clinical symptoms. While this variant is associated with an increased risk of primary congenital glaucoma, genetic factors are only one part of the health picture. If you are concerned about eye health or have a family history of glaucoma, consult an ophthalmologist for a comprehensive eye examination. Never make changes to your medical care or treatment plans based solely on genetic data without professional clinical guidance.
How common is this variant?
The rs121912646 variant is rare in the general population, with an allele frequency of approximately 0.0005, though it is more prevalent in specific Middle Eastern and North African populations.
Frequently asked questions
Is rs121912646 the only cause of congenital glaucoma?
No, primary congenital glaucoma is a genetically heterogeneous condition. While mutations in CYP1B1 are a major cause, other genes such as MYOC and TEK are also associated with the development of the disease.
Can I be a carrier of this variant and not have glaucoma?
Yes, because primary congenital glaucoma is typically an autosomal recessive disorder, carriers who have only one copy of the pathogenic variant usually do not develop the condition themselves.
What should I do if I have the A/A genotype?
If you have been identified as having the A/A genotype, you should consult with a medical geneticist or an ophthalmologist. They can provide appropriate clinical screening and discuss the implications for your eye health.
Does this variant affect how I respond to glaucoma medication?
There is no standard evidence suggesting this specific variant dictates medication response. Always discuss any concerns regarding glaucoma treatment and dosing with your clinician or pharmacist.
Sources & further reading
Educational information only, last refreshed 10/17/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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This variant (p.Asn453Ser, formerly Val432Leu) in the CYP1B1 gene is associated with altered enzyme activity and has been investigated for susceptibility to various cancers, including breast and prostate cancer.
This variant (p.Gly61Glu) is a well-documented pathogenic mutation associated with primary congenital glaucoma (PCG) and is also studied for its role in oxidative stress and drug response pathways.
A missense variant in CYP1B1 (p.Ala119Ser) associated with primary congenital glaucoma and juvenile open-angle glaucoma risk.
A well-characterized loss-of-function missense variant causing primary congenital glaucoma through abnormal trabecular meshwork development.
Missense variant in CYP1B1 associated with primary congenital glaucoma.
A classic founder missense mutation in CYP1B1 responsible for early-onset recessive infantile and juvenile glaucoma.