CFTR rs397516934: Ivacaftor Response and G551D Explained
The rs397516934 variant (frequently tracked in databases as rs75527207) is a well-characterized missense alteration in the CFTR gene leading to the p.Gly551Asp (G551D) protein change. This alteration disrupts the gating mechanism of the CFTR epithelial chloride channel, causing classic cystic fibrosis when paired with another pathogenic CFTR mutation. Importantly, this variant is the cornerstone pharmacogenomic marker for the CFTR potentiator drug ivacaftor (Kalydeco), which specifically helps keep the mutated channel open.
What each genotype means
Typical CFTR gating function
You carry two reference copies of the CFTR gene at position 551 without the G551D missense change. This genotype is associated with normal channel gating at this residue and does not indicate eligibility for ivacaftor monotherapy targeted specifically to G551D. Any medication decisions or cystic fibrosis evaluations should always be reviewed directly with your healthcare provider.
Carried by more than 99.8% of individuals globally across all major ancestral populations.
Ivacaftor-responsive G551D carrier
You carry one copy of the Class III gating variant G551D (c.1652G>A) alongside one reference allele. When paired with another disease-causing CFTR mutation in trans causing cystic fibrosis, this genotype confers clinical responsiveness to the CFTR potentiator ivacaftor (Kalydeco). You should discuss any medication regimens, dosing, or carrier implications with your doctor or clinical geneticist.
Found in approximately 1 in 1,000 individuals of European descent, with higher frequencies in Celtic populations and rare occurrence in non-European ancestries.
Ivacaftor-responsive homozygous G551D
You carry two copies of the pathogenic G551D (c.1652G>A) gating variant. In the context of cystic fibrosis, individuals with this genotype produce CFTR channels with impaired opening capability that demonstrate responsiveness to the potentiator drug ivacaftor. Consult your prescribing physician or pharmacist regarding therapy indications, monitoring, and treatment planning.
Extremely rare across all populations, estimated to occur in fewer than 1 in 1,000,000 individuals.
What the Variant Is and Where It Sits
The rs397516934 variant is located in the CFTR gene on chromosome 7. At the molecular level, it corresponds to a single-nucleotide substitution (c.1652G>A) that substitutes a glycine residue with aspartic acid at amino acid position 551 (p.Gly551Asp, commonly called G551D). In genomic repositories, this change is cataloged under rs397516934 as well as the merged dbSNP identifier rs75527207. Because CFTR encodes a multi-domain channel, this specific change falls within nucleotide-binding domain 1 (NBD1), a region essential for normal channel opening and regulation.
Biological Function of the CFTR Gene and the G551D Defect
The cystic fibrosis transmembrane conductance regulator (CFTR) protein is an epithelial cell-surface channel responsible for transporting chloride and bicarbonate ions across mucosal barriers in the lungs, pancreas, intestines, and sweat glands. Normal ion movement maintains fluid balance and keeps secretions thin. The G551D mutation represents a Class III defect, or a 'gating mutation.' Unlike Class II mutations (such as deltaF508) where the protein fails to reach the cell membrane, G551D channels successfully reach the cell surface but cannot open efficiently in response to ATP. This dramatically reduces chloride transport, producing thick, sticky mucus.
Clinical and Pharmacogenomic Evidence
While G551D is traditionally classified as a pathogenic mutation in recessive cystic fibrosis, it has gained substantial prominence in pharmacogenomics. In 2012, ivacaftor (Kalydeco) was approved as a targeted CFTR potentiator specifically designed to bind to gating-defective channels and increase their open probability. Clinical trials demonstrated marked improvements in lung function (FEV1), body mass index, and sweat chloride concentration in patients harboring at least one G551D allele. CPIC and international guidelines recognize this variant as a primary determinant for potentiator therapy, backed by robust clinical trial and real-world cohort data.
Population Frequency and Demographics
The G551D allele is rare overall in the general global population but represents one of the most common non-deltaF508 CFTR mutations. It accounts for approximately 1.5% to 3% of cystic fibrosis alleles in populations of European ancestry, with carrier frequencies estimated around 1 in 1,000 individuals. It is particularly enriched in specific regions, such as Ireland and the United Kingdom, while being exceptionally uncommon in East Asian, African, and Indigenous populations. In population databases like gnomAD, it appears at very low background frequencies due to its pathogenicity.
What You Can and Cannot Do with This Information
Finding this variant in raw genetic data should be interpreted with clinical guidance. Carrying one copy of the 'A' allele indicates carrier status for cystic fibrosis; on its own, a single copy does not cause cystic fibrosis because the condition is autosomal recessive. However, if an individual is clinically diagnosed with cystic fibrosis and carries at least one G551D allele, this genetic result serves as a critical pharmacogenomic eligibility marker for ivacaftor-based therapies. Patients should never initiate or adjust prescription therapies based on consumer data; always consult a pulmonologist, medical geneticist, or pharmacist for diagnostic confirmation and treatment decisions.
How common is this variant?
The G551D variant has an estimated carrier frequency of approximately 1 in 1,000 in European-derived populations, accounting for about 1.6% of cystic fibrosis alleles. It is exceptionally rare or absent in East Asian and African ancestries.
Frequently asked questions
What does having the CFTR G551D variant mean?
Having one copy of the G551D variant (c.1652G>A) means you are a carrier of a cystic fibrosis mutation. Because cystic fibrosis is an autosomal recessive disorder, you will not have the condition unless you also inherited a second pathogenic CFTR mutation from your other parent.
Why is the G551D mutation linked to ivacaftor (Kalydeco)?
G551D is a gating defect where the CFTR channel reaches the cell surface but stays closed. Ivacaftor works as a potentiator, binding directly to these defective channels to force them open, which restores chloride ion flow and alleviates cystic fibrosis symptoms.
Is rs397516934 the same as rs75527207?
Yes. Genomic databases sometimes assign multiple accession numbers to the same chromosomal position during initial variant discovery. Both rs397516934 and rs75527207 point to the c.1652G>A (p.Gly551Asp) missense change in CFTR.
Does carrying G551D mean I should take ivacaftor?
No. Ivacaftor is prescribed only to individuals with a verified clinical diagnosis of cystic fibrosis who carry specific responsive mutations like G551D. Asymptomatic carriers do not require or benefit from CFTR modulator therapies.
Sources & further reading
Educational information only, last refreshed 9/13/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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Severe pathogenic mutation (p.Gly542Ter) associated with cystic fibrosis.
Classic cystic fibrosis in-frame 3-bp deletion variant (p.Phe508del / deltaF508) causing misfolding and impaired chloride channel trafficking.
Pathogenic frameshift mutation (c.3659delC) in CFTR linked to cystic fibrosis.
Pathogenic nonsense variant (p.Gly542Ter / G542X) causing autosomal recessive cystic fibrosis when inherited in trans with another CFTR pathogenic allele.
Also known as p.Arg117His (R117H), this CFTR variant is associated with mild or atypical cystic fibrosis and congenital bilateral absence of the vas deferens, with clinical severity influenced by the poly-T tract background.
A CFTR mutation associated with cystic fibrosis and CFTR-related disorders.