BCHE rs28933389: Fluoride-1 Variant and Anesthesia
The rs28933389 variant is a rare missense single nucleotide polymorphism in the BCHE gene, historically known as the fluoride-resistant 1 (F1) allele. It leads to an altered pseudocholinesterase enzyme that exhibits reduced capacity to hydrolyze neuromuscular blocking agents such as succinylcholine and mivacurium. Individuals carrying this variant, particularly in homozygous or compound heterozygous states, are at an increased risk of prolonged neuromuscular blockade and post-anesthesia apnea.
What each genotype means
Typical enzyme activity
This genotype represents the most common form of the BCHE gene. Individuals with this profile typically produce normal levels of functional butyrylcholinesterase enzyme, which is responsible for breaking down certain muscle relaxants like succinylcholine and mivacurium.
This is the most common genotype found across all global populations.
Reduced enzyme activity risk
This genotype includes one copy of the F1 variant, which is associated with reduced butyrylcholinesterase activity. Carriers may have a higher risk of experiencing prolonged muscle relaxation or apnea if exposed to medications like succinylcholine or mivacurium, and should discuss this risk with their clinician or pharmacist before surgery.
This genotype is very rare, with the minor allele frequency reported as less than 0.005 globally.
High risk of deficiency
This genotype indicates the presence of two copies of the F1 variant, which is linked to significantly reduced or dysfunctional butyrylcholinesterase activity. Individuals with this profile are at an increased risk for prolonged apnea following the administration of specific neuromuscular blocking agents; please consult with your anesthesiologist or pharmacist regarding this genetic finding.
This genotype is extremely rare in the general population.
Genetic Identity and Molecular Location
The single nucleotide polymorphism rs28933389 represents a missense substitution situated within the butyrylcholinesterase (BCHE) gene on the long arm of chromosome 3 at cytogenetic position 3q26.1. At the cDNA level, the variant typically manifests as a transition from cytosine to thymine, corresponding to an altered codon in the mature enzyme sequence. In traditional biochemical literature, it is often documented as the fluoride-1 or F1 allele, frequently designated as p.Thr243Met in mature peptide numbering or p.Thr271Met (and historically p.Thr267Met) when including the leader sequence. Because the BCHE locus contains multiple qualitative and quantitative variants, precise mapping and nomenclature are essential for understanding how this amino acid substitution influences the tertiary structure and catalytic efficiency of the resulting enzyme.
Biological Function of the BCHE Gene
The BCHE gene directs the production of butyrylcholinesterase, also commonly called pseudocholinesterase or plasma cholinesterase. Produced primarily by hepatocytes in the liver and subsequently secreted into the circulating blood plasma, this serine hydrolase serves as a vital metabolic scavenger. Under typical physiological conditions, pseudocholinesterase rapidly cleaves choline esters and xenobiotic compounds. Its most notable clinical duty involves hydrolyzing short-acting depolarizing and non-depolarizing neuromuscular blocking agents administered during tracheal intubation and general anesthesia, such as succinylcholine and mivacurium. When functioning normally, the enzyme inactivates succinylcholine within minutes, permitting patients to recover spontaneous respiration rapidly after surgical airway procedures.
Pharmacogenomic Impact and Strength of Evidence
Biochemically, the rs28933389 substitution produces an enzyme variant characterized by resistance to inhibition by sodium fluoride in standard laboratory assays, paired with reduced catalytic efficiency toward choline ester substrates. The clinical evidence cataloged in pharmacogenomic resources such as PharmGKB and ClinVar associates the minor allele with butyrylcholinesterase deficiency and prolonged post-anesthetic apnea. When administered standard clinical doses of succinylcholine or mivacurium, individuals harboring this variant in combination with other loss-of-function alleles (such as the atypical or silent alleles) or in a homozygous state experience significantly extended periods of paralysis, sometimes lasting several hours instead of minutes. However, because rs28933389 is exceedingly rare in the general population, overall observational sample sizes remain limited, and single heterozygous carriers often display only mild or subclinical enzyme reductions unless paired with another defective allele.
Ancestral Diversity and Allele Frequency
Data from large-scale genomic databases, including gnomAD and clinical cohort studies, demonstrate that rs28933389 is an exceptionally uncommon variant globally. The minor allele frequency consistently measures well below 0.5% (MAF < 0.005) across all major continental ancestral populations, with some multi-ethnic clinical screening cohorts reporting frequencies around 0.08%. True homozygosity for the fluoride-1 allele is estimated to occur in fewer than one in 100,000 to 150,000 individuals. Because of its scarcity, routine population screening has historically not been standard practice, and the variant is usually uncovered only through targeted pharmacogenetic panels or following an unexpected clinical episode of delayed emergence from neuromuscular relaxation.
Clinical Considerations and Actionable Limits
Knowledge of an rs28933389 carrier status is strictly educational and pharmacogenomic; it is not a diagnosis of disease, as individuals with pseudocholinesterase variants typically lead healthy lives free of spontaneous symptoms. The primary relevance surfaces exclusively in settings where choline ester muscle relaxants are deployed. Individuals who discover they carry an altered BCHE variant should discuss their results with their physician, anesthesiologist, or clinical pharmacist prior to undergoing planned surgical procedures. Anesthesia providers can readily adapt by selecting alternative non-depolarizing paralytic agents, such as rocuronium paired with reversal agents like sugammadex, or by monitoring neuromuscular transmission until spontaneous ventilation is fully restored.
How common is this variant?
The rs28933389 variant is exceptionally rare across all surveyed continental populations, exhibiting a global minor allele frequency well below 0.005 (0.5%) in gnomAD and roughly 0.08% in large clinical pharmacogenomic cohorts.
Frequently asked questions
What is the BCHE rs28933389 variant?
The rs28933389 SNP is a rare genetic alteration in the BCHE gene that produces the fluoride-resistant 1 (F1) form of pseudocholinesterase. This altered enzyme exhibits reduced hydrolytic activity toward specific surgical muscle relaxants.
Does having this variant cause everyday health problems?
No, carrying the rs28933389 variant does not cause chronic illness, physical discomfort, or spontaneous medical issues. Its effects remain clinically silent unless an individual receives specific anesthesia medications during a medical procedure.
Which medications are affected by the rs28933389 SNP?
This variant primarily affects the clearance of choline ester muscle relaxants, notably succinylcholine and mivacurium. Individuals with significantly reduced enzyme activity take much longer to break down these drugs, leading to prolonged muscle paralysis.
What should I do if my genetic test shows this variant?
You should share and discuss your genetic test report with your physician, anesthesiologist, or clinical pharmacist before any surgery requiring anesthesia. Anesthesiologists can easily select alternative paralytics that do not rely on butyrylcholinesterase for clearance.
Can blood tests detect pseudocholinesterase deficiency?
Yes, specialized biochemical laboratory tests can measure both the overall concentration and functional activity of butyrylcholinesterase in plasma. These biochemical tests often use chemical inhibitors, such as dibucaine and fluoride, to confirm qualitative enzyme abnormalities.
Sources & further reading
Educational information only, last refreshed 9/5/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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A variant in the BCHE gene associated with butyrylcholinesterase activity levels.
Encodes the atypical A variant (Asp70Gly) of butyrylcholinesterase which drastically prolongs muscle paralysis after standard doses of mivacurium or succinylcholine.
Defines the BCHE atypical (A) variant (p.Asp70Gly) that causes prolonged paralysis and apnea following exposure to neuromuscular blockers such as succinylcholine or mivacurium.
Defines the BCHE fluoride-resistant (F2, p.Gly418Arg) allele that leads to impaired hydrolysis of mivacurium and succinylcholine, increasing prolonged post-anesthesia apnea risk.
Commonly known as the BCHE atypical variant (Asp70Gly), this single nucleotide change reduces pseudocholinesterase enzyme activity, affecting drug metabolism in obstetric anesthesia and reproduction-related surgical procedures.