FANCC rs121908226: Understanding the c.456+4A>T Variant
The rs121908226 variant, also known as c.456+4A>T, is a pathogenic genetic change located within the FANCC gene. It is primarily recognized for its association with Fanconi anemia, a rare inherited disorder characterized by bone marrow failure and increased cancer risk.
What each genotype means
Typical FANCC genotype
This genotype represents the common, non-variant sequence at this position in the FANCC gene. It is not associated with the specific pathogenic splice variant linked to Fanconi anemia complementation group C.
This is the most common genotype found in the general population across all ancestries.
FANCC carrier status
You carry one copy of the c.456+4A>T variant, which is a known pathogenic splice mutation in the FANCC gene. Carriers are typically asymptomatic, but this variant is associated with an increased risk of having a child with Fanconi anemia if a partner also carries a pathogenic FANCC variant. You may wish to discuss reproductive carrier screening options with a genetic counselor.
This genotype is carried by approximately 1 in 90 individuals of Ashkenazi Jewish ancestry.
Potential Fanconi anemia risk
This genotype indicates the presence of two copies of the pathogenic c.456+4A>T variant. This variant is associated with Fanconi anemia complementation group C, a condition that can affect bone marrow function and increase cancer risk. Please consult with a medical geneticist or healthcare provider to discuss clinical implications and appropriate follow-up.
This genotype is extremely rare in the general population.
What is the rs121908226 Variant?
The variant rs121908226, often referred to in clinical literature as c.456+4A>T or IVS4+4A>T, is a single nucleotide change located in the FANCC gene. This specific mutation occurs in an intronic region, which is the non-coding part of a gene that is typically removed during the process of creating a functional protein. Because this variant sits at a critical splice site—the boundary where the cell machinery cuts and joins genetic instructions—it can disrupt the normal splicing process. When splicing is disrupted, the resulting protein may be truncated, unstable, or entirely non-functional. This variant is classified as pathogenic, meaning it is known to cause disease when inherited in a specific pattern. It is important to note that this variant is distinct from other genetic markers and is specifically linked to the disruption of the FANCC protein's role in cellular maintenance.
The Role of the FANCC Gene
The FANCC gene provides the blueprint for the Fanconi anemia group C protein. This protein is a vital component of the Fanconi anemia (FA) core complex, a group of proteins that work together to repair damaged DNA. Specifically, the FA pathway is essential for fixing interstrand crosslinks, which are a type of DNA damage that can prevent cells from dividing correctly. When the FANCC protein is absent or dysfunctional, the cell's ability to repair its own DNA is severely compromised. This leads to genomic instability, where errors accumulate in the DNA over time. This instability is the underlying cause of the clinical features seen in Fanconi anemia, including bone marrow failure, where the body stops producing enough blood cells, and a significantly increased susceptibility to various types of cancer, particularly leukemia and head and neck squamous cell carcinomas.
Research and Clinical Associations
Research into rs121908226 is grounded in its role as a founder mutation within the Ashkenazi Jewish population. Fanconi anemia is an autosomal recessive condition, 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 show symptoms of the condition. Clinical studies have identified this variant as a significant contributor to the genetic burden of Fanconi anemia in specific ancestral groups. While the evidence linking this specific splice site mutation to the disease is strong, the clinical presentation of Fanconi anemia can be highly variable even among individuals with the same genotype. This variability is due to a combination of genetic modifiers, environmental factors, and the specific nature of the mutation's impact on protein function. Current research continues to focus on how these molecular defects translate into the diverse clinical outcomes observed in patients.
Population Frequency
The rs121908226 variant is most notably observed in the Ashkenazi Jewish population, where it is estimated to have a carrier frequency of approximately 1 in 90. This higher frequency is attributed to founder effects, where a small ancestral population expanded, leading to the increased prevalence of certain genetic variants. Because it is a recessive condition, the risk of having a child with Fanconi anemia is significantly higher when both parents are carriers of a pathogenic FANCC variant. Outside of this specific population, the variant is extremely rare. Genetic screening programs often include this variant when testing for common recessive conditions in individuals of Ashkenazi Jewish descent to provide information regarding reproductive risk. It is not a common variant in the general global population, and its presence is generally screened for in the context of targeted carrier testing rather than broad population-wide genomic surveys.
What This Information Means for You
If you have received information regarding your status for the rs121908226 variant, it is important to understand that this is a carrier status result. Being a carrier means you have one copy of the variant and are generally healthy, as the condition is recessive. However, if your partner is also a carrier of a pathogenic FANCC variant, there is a 25% chance for each pregnancy that the child will inherit two copies and potentially develop Fanconi anemia. This information is intended for educational purposes and should not be used for self-diagnosis. If you are concerned about your carrier status or family history, the most appropriate step is to consult with a certified genetic counselor or a medical geneticist. These professionals can help interpret your results in the context of your personal and family history, discuss the implications for family planning, and provide guidance on whether clinical testing is necessary for you or your relatives.
How common is this variant?
The carrier frequency for this variant is approximately 1 in 90 in the Ashkenazi Jewish population, while it remains extremely rare in other global populations.
Frequently asked questions
Is rs121908226 the same as having Fanconi anemia?
No. Having one copy of this variant makes you a carrier, which typically does not cause symptoms. Fanconi anemia is a recessive condition that usually requires inheriting two pathogenic variants.
Should I be worried if I am a carrier?
Being a carrier is common for many recessive conditions and does not affect your own health. However, it is useful information for family planning, and you may want to discuss it with a genetic counselor.
How is this variant tested?
This variant is typically identified through targeted genetic carrier screening or clinical sequencing of the FANCC gene. These tests are usually ordered by a healthcare provider.
Does this variant increase my cancer risk?
As a carrier, there is no evidence that you have an increased risk of cancer. The increased cancer risk is associated with individuals who have two pathogenic variants and the resulting Fanconi anemia.
Sources & further reading
Educational information only, last refreshed 9/28/2026. Not medical advice — these associations describe population statistics, not individual predictions.
Curious what your genotype is for rs121908226?
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 — $29