GNRHR rs1126761: Understanding the p.Gln106Arg Variant
The rs1126761 variant, also known as p.Gln106Arg, is a missense mutation in the GNRHR gene. It is primarily studied for its association with autosomal recessive normosmic idiopathic hypogonadotropic hypogonadism (nIHH) and delayed puberty when present in a compound heterozygous or homozygous state.
What each genotype means
Typical reproductive development
You carry two copies of the standard allele for the GNRHR receptor. Research indicates standard receptor signaling and normal hypothalamic-pituitary-gonadal axis function without an increased risk for receptor-related pubertal delay.
Carried by approximately 94% to 99% of individuals across global populations, being most common in non-European ancestries.
Carrier of reproductive variant
You carry one copy of the p.Gln106Arg missense variant in the GNRHR gene. Carriers generally experience typical pubertal timing and normal fertility, as condition inheritance is autosomal recessive; clinical symptoms such as delayed puberty or hypogonadotropic hypogonadism typically only manifest if a second pathogenic variant is present in GNRHR or related reproductive genes.
Carried by roughly 1% to 3% of individuals of European ancestry and reaches up to 6% in specific founder populations such as Malta, but is rare in East Asian and African ancestries.
Altered gonadotropin receptor signaling
You carry two copies of the p.Gln106Arg variant, which reduces binding affinity and signaling of the gonadotropin-releasing hormone receptor. In clinical studies, this genotype has been associated with constitutional delay of puberty or mild to incomplete isolated hypogonadotropic hypogonadism, though phenotypes vary and some individuals experience spontaneous pubertal progression.
Extremely rare globally, occurring in fewer than 1 in 10,000 individuals, but slightly elevated in populations with higher carrier frequencies.
What is the rs1126761 Variant?
The rs1126761 variant is a single nucleotide polymorphism (SNP) located within the GNRHR gene, which encodes the gonadotropin-releasing hormone receptor. In this specific variant, a genetic change results in the substitution of the amino acid glutamine with arginine at position 106 of the protein (p.Gln106Arg). This change occurs in the first extracellular loop of the receptor, a critical region for the binding of gonadotropin-releasing hormone (GnRH). Because this receptor is essential for the signaling pathways that trigger the release of reproductive hormones, alterations in its structure can disrupt normal physiological processes. Researchers identify this as a missense variant, meaning the DNA change alters the protein's primary sequence, which may subsequently affect its ability to function correctly within the pituitary gland.
The Role of the GNRHR Gene
The GNRHR gene provides instructions for making the gonadotropin-releasing hormone receptor, a G-protein-coupled receptor found on the surface of pituitary cells. This receptor acts as a gatekeeper for the reproductive system; when GnRH binds to it, the receptor initiates a cascade of intracellular signals that lead to the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones are vital for the development of secondary sexual characteristics, the regulation of the menstrual cycle, and the production of sperm. When the GNRHR protein is dysfunctional, the pituitary gland may fail to release sufficient amounts of these hormones, leading to a condition known as hypogonadotropic hypogonadism. This condition is characterized by delayed or absent puberty and potential infertility, highlighting the gene's fundamental role in human reproductive development.
Research and Clinical Associations
Scientific literature consistently identifies rs1126761 as one of the most common pathogenic alleles associated with normosmic idiopathic hypogonadotropic hypogonadism (nIHH). Research indicates that this variant, particularly when inherited in a compound heterozygous state (paired with another pathogenic GNRHR mutation) or a homozygous state, impairs the receptor's ability to bind GnRH and transmit signals effectively. While the evidence for its role in severe reproductive phenotypes is strong, the clinical presentation can be highly variable, even among family members with the same genotype. Some individuals may experience permanent hypogonadism, while others might show signs of constitutional delay of puberty. It is important to note that the presence of this variant does not guarantee a specific clinical outcome, and its impact is often dependent on the presence of other genetic factors or the specific combination of alleles inherited.
Population Frequency
The rs1126761 variant is considered a rare to low-frequency variant in the general population. Data from large-scale genomic databases indicate that the minor allele frequency typically ranges between 0.015 and 0.03 in European populations. Because it is a recessive trait, the occurrence of the associated clinical conditions is significantly lower than the frequency of the variant itself, as an individual would generally need to inherit two copies of a pathogenic allele to manifest the condition. The distribution of this variant varies across different ancestral groups, and researchers continue to study how these frequencies correlate with the prevalence of reproductive health conditions globally.
Interpreting Your Genetic Information
Understanding your genetic status regarding rs1126761 should be approached with care. This information is intended for educational purposes and does not constitute a medical diagnosis. If you have concerns about pubertal development, fertility, or reproductive health, it is essential to consult with a qualified healthcare provider or a genetic counselor. They can interpret your results in the context of your personal and family medical history. Genetic testing for this variant is typically reserved for clinical settings where there is a suspected underlying genetic cause for hypogonadism. Never use this information to make decisions about medical treatments or hormone therapies without professional guidance. A clinician can help determine if further diagnostic testing is appropriate and discuss the implications of your specific genetic profile.
How common is this variant?
The minor allele frequency for rs1126761 is approximately 0.015 to 0.03 in European populations, making it a relatively uncommon variant.
Frequently asked questions
Is rs1126761 the same as Gln106Arg?
Yes, rs1126761 is the identifier for the specific genetic location, while p.Gln106Arg describes the resulting change in the protein sequence where glutamine is replaced by arginine.
Does having the GG genotype mean I am infertile?
Not necessarily. While the GG genotype is associated with GNRHR-related hypogonadism, clinical outcomes are highly variable. You should discuss your specific health history with a reproductive endocrinologist.
Can this variant cause delayed puberty?
Yes, research has linked GNRHR variants to both constitutional delay of puberty and idiopathic hypogonadotropic hypogonadism. However, many factors influence pubertal timing, and this variant is only one potential contributor.
Is this condition inherited?
Yes, GNRHR-related conditions are typically inherited in an autosomal recessive pattern. This means an individual usually needs to inherit two copies of a pathogenic variant to be affected.
Sources & further reading
Educational information only, last refreshed 10/19/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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This synonymous variant in the gonadotropin-releasing hormone receptor gene is studied for its potential role in modulating reproductive hormone responsiveness.
Pathogenic missense substitution (p.Arg262Gln) in GNRHR linked to autosomal recessive normosmic congenital hypogonadotropic hypogonadism.
Gonadotropin-releasing hormone receptor variant associated with altered gonadotropin pulsatility and susceptibility to delayed puberty.
Recessive pathogenic missense variant in gonadotropin-releasing hormone receptor causing normosmic idiopathic hypogonadotropic hypogonadism and delayed puberty.
A missense variant (p.Gln106Arg) in the gonadotropin-releasing hormone receptor associated with normosmic congenital hypogonadotropic hypogonadism.
Pathogenic missense variant disrupting GnRH binding in the pituitary gonadotropes, causing severe hypogonadotropic hypogonadism.