PRF1 rs193302875: Familial HLH Carrier Status
The rs193302875 single nucleotide polymorphism is a rare missense variation located in exon 3 of the PRF1 gene, resulting in a serine-to-isoleucine substitution at amino acid position 388 (p.Ser388Ile). Clinically, this variant is cataloged as a carrier allele associated with autosomal recessive familial hemophagocytic lymphohistiocytosis type 2 (FHL2) and has occasionally appeared in studies of immune dysfunction such as aplastic anemia. Because FHL2 is inherited in a recessive pattern, carrying a single altered copy generally does not cause disease on its own.
What each genotype means
Typical PRF1 genotype
This genotype represents the most common sequence found at this position in the PRF1 gene. It is not associated with the specific pathogenic variant linked to familial hemophagocytic lymphohistiocytosis type 2.
This is the most common genotype observed in the general population.
PRF1 variant carrier
You carry one copy of the p.Ser388Ile variant in the PRF1 gene. While this variant is considered pathogenic in the context of autosomal recessive familial hemophagocytic lymphohistiocytosis type 2, carriers typically do not exhibit symptoms of the condition, as the disease generally requires two pathogenic copies. Please consult with a genetic counselor or physician to discuss the implications of this carrier status.
This genotype is rare, with the variant allele frequency reported as less than 0.001 in global populations.
Potential PRF1-related risk
This genotype indicates the presence of two copies of the p.Ser388Ile variant. This variant is classified as pathogenic and is associated with autosomal recessive familial hemophagocytic lymphohistiocytosis type 2, a condition that can affect immune system function. It is important to discuss these results with a medical professional or clinical geneticist to understand your specific health context.
This genotype is extremely rare in the general population.
Genomic Context and the PRF1 Gene
The PRF1 gene is situated on chromosome 10 and provides the genetic blueprint for perforin 1, a critical cytolytic protein expressed primarily by cytotoxic T lymphocytes and natural killer (NK) cells. Under normal physiological conditions, perforin forms pores in the plasma membranes of target cells—such as virus-infected or abnormal cells—allowing pro-apoptotic granzymes to enter and trigger programmed cell death. The rs193302875 polymorphism, identified at cDNA position c.1163G>T, causes a missense alteration changing a serine residue to an isoleucine at position 388 (p.Ser388Ile). Alterations in the functional domains of perforin can impair pore formation, preventing effective cytotoxic clearance. When immune cells cannot effectively eliminate targeted cells, the normal negative feedback loops that wind down immune reactions fail, potentially precipitating life-threatening hyperinflammatory cascades.
Clinical Significance and Disease Association
Biallelic mutations in PRF1—meaning pathogenic variants on both inherited chromosomes—are the primary cause of familial hemophagocytic lymphohistiocytosis type 2 (FHL2). FHL2 is an autosomal recessive, hyperinflammatory condition characterized by prolonged unremitting fever, severe cytopenias, splenomegaly, and uncontrolled immune activation. Carrier status (heterozygosity for rs193302875) implies having one affected allele alongside a functioning copy. In scientific literature and clinical databases such as OMIM and ClinVar, rs193302875 has been reported in patients evaluated for aplastic anemia and suspected atypical immune dysregulation. However, overall published evidence connecting this specific missense alteration across broad populations remains limited. Carrying one mutated copy is not sufficient to diagnose or predict familial HLH, as clinical manifestation virtually always requires a second severe mutation in PRF1 or a complex multi-gene defect.
Population Frequency and Scientific Evidence
Data from large genomic aggregation cohorts, including gnomAD, indicate that rs193302875 is an exceptionally rare allele worldwide, with a global minor allele frequency (MAF) well below 0.001 (less than 0.1%). It has been observed in low counts across diverse ancestral backgrounds, including Hispanic and European populations, but remains absent or extremely scarce in most general sequencing panels. Because the variant is so infrequent, population-level penetrance calculations and clear-cut risk ratios are unavailable. In clinical classification frameworks like ACMG guidelines, rare missense variants with low observation counts often sit in categories ranging from variants of uncertain significance (VUS) to pathogenic when found in trans with known deleterious mutations in affected probands. Consequently, researchers continue to evaluate rs193302875 primarily in specialized hematology and immunology settings.
Interpreting Results and Clinical Perspective
Discovering an rs193302875 variant on a direct-to-consumer genetic test or an expanded carrier screening panel often causes undue alarm. It is vital to recognize that carrier status for a recessive disorder does not constitute an active medical diagnosis. Most heterozygous carriers lead healthy lives with fully functional immune systems, as a single working copy of PRF1 typically supplies sufficient perforin activity for routine cellular defense. These data cannot be used to predict routine infections, auto-immune complaints, or medication responses. Anyone concerned about carrier status, particularly prospective parents planning a family or individuals with a strong personal or family history of unexplained infant cytopenias and hyperinflammation, should discuss these findings with a certified genetic counselor or clinical geneticist.
How common is this variant?
The rs193302875 variant is extremely rare globally, exhibiting an overall minor allele frequency (MAF) of less than 0.001 across the gnomAD dataset. Homozygous individuals are exceedingly uncommon in unselected public population databases.
Frequently asked questions
What does being a carrier of PRF1 rs193302875 mean?
Being a carrier means you have one copy of the rare variant and one standard copy of the PRF1 gene. Because familial hemophagocytic lymphohistiocytosis type 2 is an autosomal recessive condition, carriers generally do not develop the disease itself.
Can rs193302875 cause familial hemophagocytic lymphohistiocytosis alone?
No, a single heterozygous copy of rs193302875 is not sufficient to cause familial hemophagocytic lymphohistiocytosis. Developing this genetic disorder requires inheriting two pathogenic variants—one on each PRF1 chromosome—or having other severe compounding genetic defects.
Does this genetic variant affect how I respond to common medications?
Currently, there is no evidence indicating that rs193302875 alters drug metabolism or requires specific pharmaceutical dosing adjustments. Any questions regarding medications or adverse reactions should always be discussed directly with a physician or pharmacist.
Should my family members be tested if I carry this variant?
If you are confirmed to carry the variant through a validated clinical test, reproductive partners may consider carrier screening to assess the risk for future children. A genetic counselor can review your family history and recommend appropriate testing protocols.
Sources & further reading
Educational information only, last refreshed 9/6/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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