Cystic fibrosis is caused by mutations in a single gene called CFTR, located on chromosome 7. The most common mutation, known as F508del, accounts for roughly 80% of all cystic fibrosis cases. But over 2,100 mutations have been identified in the CFTR gene so far, with 719 confirmed to actually cause disease.
What the CFTR Gene Normally Does
The CFTR gene provides instructions for building a protein that acts as a channel on the surface of cells. This channel moves chloride ions (a component of salt) into and out of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. That chloride transport controls how much water flows into those secretions, keeping them thin and slippery. The CFTR protein also helps regulate separate sodium channels on cell membranes, giving it a broad role in maintaining the salt and water balance across many tissues.
When the CFTR protein works correctly, the mucus lining your airways, digestive tract, and other organs stays fluid enough to move freely. When it doesn’t, the consequences ripple across multiple organ systems.
The F508del Mutation
F508del is a deletion of just three DNA letters, which removes a single amino acid (phenylalanine) at position 508 of the CFTR protein. That tiny change is enough to cause the protein to fold incorrectly. Your cells have a quality-control system inside a structure called the endoplasmic reticulum, and it recognizes the misfolded protein as defective. Molecular chaperones, which normally help proteins fold, instead trap the abnormal CFTR and tag it for destruction. The result: very little functional CFTR protein ever reaches the cell surface.
About 80% of people with cystic fibrosis carry at least one copy of F508del. Many are homozygous, meaning they inherited the same mutation from both parents. Others carry F508del on one chromosome and a different CFTR mutation on the other.
Six Classes of CFTR Mutations
Because so many different mutations can disrupt the CFTR protein, scientists group them into six classes based on what goes wrong at the cellular level. Understanding which class a person’s mutation falls into matters because it shapes which treatments are most likely to help.
- Class I: No protein produced. These mutations introduce a premature “stop” signal in the gene, so cells make little or no CFTR protein at all.
- Class II: Protein misfolds and gets destroyed. F508del belongs here. The protein is made but folds incorrectly, so the cell’s quality-control system breaks it down before it reaches the surface.
- Class III: Protein reaches the surface but won’t open. The channel arrives at the cell membrane but has a gating defect, meaning it rarely opens to let chloride through. The mutation G551D is a well-known example.
- Class IV: Channel opens but conducts poorly. The protein makes it to the surface and opens, but the pore is altered so fewer chloride ions pass through.
- Class V: Too little protein made. The protein itself is normal, but errors in gene regulation mean cells produce much less of it than they should.
- Class VI: Protein is unstable at the surface. The channel reaches the cell membrane but breaks down quickly, so it doesn’t stay in place long enough to do its job.
Classes I through III generally cause the most severe disease because they result in little or no functioning chloride transport. Classes IV through VI tend to allow some residual CFTR activity, which can mean milder symptoms, though this varies considerably from person to person.
Other Common Mutations Beyond F508del
While F508del dominates, several other mutations appear frequently enough to be clinically significant. G551D, a class III gating mutation, is found in roughly 3% of people with cystic fibrosis in some populations. G542X is a class I nonsense mutation that halts protein production entirely. R553X is another class I mutation with a similar effect. The frequency of each mutation varies by ethnic background and geographic region, which is one reason genetic testing panels have expanded over time.
How CFTR Mutations Affect the Body
A faulty CFTR protein disrupts salt and water movement across cell membranes, and that single problem cascades into thick, sticky mucus throughout the body. In the lungs, this dense mucus clogs the airways, creates a breeding ground for bacteria, and triggers chronic inflammation that progressively damages lung tissue. Breathing becomes harder over time, and repeated infections are the hallmark of the disease.
In the digestive system, thick secretions block ducts in the pancreas, preventing digestive enzymes from reaching the intestines. This leads to poor absorption of fats and nutrients, which is why many people with cystic fibrosis need enzyme supplements with every meal. The liver, intestines, and reproductive organs can also be affected. In the sweat glands, the process works differently: faulty CFTR means the body can’t reabsorb salt from sweat, so people with cystic fibrosis have unusually salty sweat. This is actually the basis for the sweat chloride test used in diagnosis.
Inheritance Pattern
Cystic fibrosis follows an autosomal recessive pattern, meaning a child must inherit a defective copy of the CFTR gene from each parent to develop the disease. If both parents are carriers (each carrying one normal copy and one mutated copy), there’s a 25% chance with each pregnancy that the child will have cystic fibrosis, a 50% chance the child will be a carrier without symptoms, and a 25% chance the child won’t carry the mutation at all.
Carriers, who have one working copy of CFTR, typically produce enough functional protein to avoid symptoms entirely. This is why cystic fibrosis can appear in families with no prior history of the disease: both parents can unknowingly pass along a mutation they never knew they had.
Genetic Testing and Screening
Standard carrier screening panels previously tested for 23 or more of the most common disease-causing CFTR mutations. Current panels typically screen for many more, though no test covers all 2,100-plus identified variants. A small chance remains that someone could carry a rare mutation not included in the panel. For people with a family history of cystic fibrosis or inconclusive screening results, full CFTR gene sequencing can detect rarer mutations that standard panels miss.
Newborn screening programs in many countries now test for cystic fibrosis shortly after birth, using a combination of blood tests and, if needed, genetic analysis. Early identification allows treatment to begin before significant lung or digestive damage occurs, which substantially improves long-term outcomes.