GJB2 rs80338939 (c.35delG): What Your Carrier Genotype Means
The genetic variant rs80338939, conventionally known in clinical genetics as c.35delG, is a single-base deletion within the GJB2 gene on chromosome 13. It is the most common founder mutation causing autosomal recessive nonsyndromic sensorineural hearing loss (DFNB1A) in individuals of European ancestry. As an autosomal recessive condition, carrying a single altered copy generally does not affect personal hearing, but carrying two pathogenic alleles typically leads to congenital hearing loss.
What each genotype means
Typical risk profile
You carry two normal copies of the GJB2 gene at this position and do not carry the c.35delG deletion. This genotype does not increase your risk of autosomal recessive nonsyndromic sensorineural hearing loss (DFNB1A) or your chance of passing this specific variant to biological offspring. It does not rule out hearing loss caused by variants at other genetic loci or environmental factors.
Carried by more than 97% to 98% of individuals across European populations and virtually all individuals of East Asian and African ancestry.
Carrier status
You have one normal copy and one deletion copy (commonly written in medical literature as c.35delG) in the GJB2 gene. Carriers are generally asymptomatic with standard hearing function because DFNB1A is inherited in an autosomal recessive manner, though some research notes subtle differences at ultra-high frequencies. If your reproductive partner is also a carrier of a pathogenic GJB2 variant, there is a 25% chance with each pregnancy of having a child with hearing loss, making genetic counseling useful for family planning.
Carried by approximately 1 in 30 to 1 in 50 individuals in Southern and Southeastern Europe, around 1 in 70 in Northern Europe, and is extremely rare in East Asian and African ancestries.
What Is rs80338939 and Where Is It Located?
The variant rs80338939 represents a frameshift deletion within the coding region of the GJB2 gene, situated on chromosome 13q12.11. In standard Human Genome Variation Society (HGVS) nomenclature, it is designated as NM_004004.6:c.35delG (p.Gly12ValfsTer2). At the molecular level, this change involves the loss of a single guanine nucleotide from a short homopolymeric run of six guanines spanning positions 30 to 35 of the coding sequence. Because this deletion disrupts the triplet reading frame of the transcript, it introduces a premature translation termination codon just two codons downstream. This leads to a severely truncated, non-functional protein product or the degradation of the transcript via nonsense-mediated decay. The variant is cataloged in dbSNP as rs80338939 and is extensively documented in ClinVar under variation ID 17004. In carrier status screening and reproductive counseling panels, it is frequently reported as 35delG or c.35delG due to its well-established clinical significance.
The Biological Role of the GJB2 Gene and Connexin 26
The GJB2 gene provides the instructions for synthesizing a transmembrane gap junction protein called connexin 26 (Cx26). In the human cochlea, six connexin subunits assemble to form a hemichannel, termed a connexon, which docks with an opposing connexon on an adjacent supporting cell. These interconnected channels create a vital intercellular network responsible for potassium ion recycling and inner ear homeostasis. During the perception of sound, mechanical stimulation of cochlear hair cells generates an inward flow of potassium ions, which depolarizes the sensory cells and propagates electrical signals along the auditory nerve. Rapid and continuous removal of potassium from the sensory hair cells and its return to the endolymph via gap junctions is necessary to prevent excitotoxic accumulation and maintain auditory sensitivity. When a frameshift variant like c.35delG abolishes connexin 26 production, this ionic communication breaks down, leading to cellular dysfunction within the organ of Corti and resulting in sensorineural hearing impairment.
Clinical Significance and Strength of Evidence
Decades of clinical literature and entries in databases like ClinVar and GeneReviews firmly classify rs80338939 as pathogenic for autosomal recessive nonsyndromic hearing loss 1A (DFNB1A). Evidence supporting this link is conclusive and verified across tens of thousands of individuals worldwide. Because inheritance is strictly autosomal recessive, individuals who inherit two copies of c.35delG—or one copy of c.35delG alongside another pathogenic GJB2 variant, such as c.167delT or a GJB6 deletion—typically manifest bilateral, sensorineural hearing loss that is present at birth or detected during infant screening. The clinical severity of this hearing loss often ranges from moderate to profound, reflecting the complete loss of function produced by a truncating allele. By contrast, individuals who inherit only a single copy of rs80338939 along with a functional reference allele are asymptomatic carriers. Peer-reviewed cohorts show that heterozygous carriers develop normal auditory acuity and do not experience premature sensorineural hearing impairment related to this carrier state.
Population Frequency and Founder Dynamics
The rs80338939 deletion displays striking geographic clustering due to historical founder effects that originated in the Mediterranean basin. In Southern and Southeastern European populations, including Greek, Italian, and Romanian cohorts, carrier frequencies are among the highest in the world, commonly estimated between 1 in 30 and 1 in 50 individuals (carrier rates of approximately 2% to 3.5%). Across Northern and Western European populations, carrier prevalence remains elevated, often cited between 1 in 40 and 1 in 100. In contrast, rs80338939 is relatively rare or absent in individuals of predominantly East Asian, African, and Indigenous American ancestry, where distinct pathogenic variants predominate. For instance, the missense variant p.Val37Ile and the truncating allele c.235delC are far more common causes of DFNB1A in East Asian cohorts, whereas the p.Arg143Trp mutation is more widespread in parts of West Africa. These population disparities emphasize the role of ancestral background when assessing carrier risk.
Navigating Results: What This Genetic Information Means
Discovering an rs80338939 variant on a direct-to-consumer or laboratory carrier screening panel is informative primarily for family planning and reproductive genetics. Carrying one altered allele indicates that you are a healthy carrier; it does not indicate that you are losing your hearing or require auditory treatment. However, if two reproductive partners are both carriers of a pathogenic GJB2 variant, there is a 25% chance with each pregnancy of having a child with autosomal recessive nonsyndromic hearing loss, a 50% chance of having a child who is also an asymptomatic carrier, and a 25% chance of having a non-carrier child. If you carry this allele, clinical genetic counselors can assist in arranging partner screening, reviewing reproductive choices, or evaluating newborn hearing test protocols. Commercial direct-to-consumer genetic panels may also occasionally produce false positives or lack comprehensive sequencing of other hearing loss loci, making clinical-grade diagnostic confirmation an essential step before making reproductive decisions.
How common is this variant?
The rs80338939 (c.35delG) deletion is one of the most common recessive pathogenic alleles in Europe, with heterozygous carrier frequencies reaching approximately 1 in 30 to 1 in 50 in Southern and Southeastern Europe. In East Asian, African, and Indigenous populations, the variant is exceptionally rare, where other population-specific GJB2 variants account for the majority of genetic hearing loss.
Frequently asked questions
Does being a carrier for rs80338939 mean my hearing will deteriorate?
No. Carrying a single copy of the c.35delG variant does not cause hearing loss. Individuals with one normal copy of the GJB2 gene produce sufficient connexin 26 protein to maintain normal cochlear potassium transport and standard hearing thresholds.
What is the likelihood of having a child with hearing loss if I am a carrier?
If your reproductive partner does not carry a pathogenic GJB2 variant, your children will have normal hearing (though each child will have a 50% chance of inheriting your carrier status). If both biological parents carry a pathogenic GJB2 allele, each pregnancy carries a 25% chance of resulting in congenital nonsyndromic hearing loss.
Why is this variant called both rs80338939 and c.35delG?
The label rs80338939 is the official database identifier assigned by the National Center for Biotechnology Information (dbSNP). The term c.35delG is standard clinical HGVS nomenclature describing the exact mutation: the deletion of a guanine nucleotide at coding position 35 of the GJB2 gene transcript.
Are there other symptoms associated with GJB2 hearing loss?
No. The hearing loss caused by biallelic c.35delG mutations is nonsyndromic, meaning it affects only auditory function without impacting the heart, kidneys, vision, or other organ systems. While a few rare dominant GJB2 variants can cause skin disorders, rs80338939 is strictly restricted to nonsyndromic sensorineural hearing loss.
Sources & further reading
Educational information only, last refreshed 9/12/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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Also known as 35delG, this frameshift mutation is a major cause of autosomal recessive nonsyndromic sensorineural hearing loss.
Pathogenic nonsense variant (p.Trp24Ter) in GJB2, representing one of the major causative alleles for autosomal recessive non-syndromic hearing loss in Mediterranean and South Asian groups.
This variant is associated with autosomal recessive nonsyndromic hearing loss.
Missense variant (p.Arg127His) in the GJB2 gene. While often reported in individuals with hearing loss, it is frequently classified as benign or likely benign in clinical databases when found in isolation, as it is common in the general population.
A missense variant (c.109G>A, p.Val37Ile) in GJB2, often identified as a common pathogenic variant associated with mild to moderate autosomal recessive nonsyndromic hearing loss (DFNB1A).
Frameshift deletion (c.235delC) conferring carrier status for autosomal recessive non-syndromic sensorineural hearing loss.