APOL1 rs73284431: The G2 Kidney Risk and Immunity Allele
The genetic variant rs73284431 is an in-frame deletion in the APOL1 gene that defines the well-studied G2 risk allele. Arising in sub-Saharan Africa, this evolutionary variant provides immunity against Trypanosoma brucei rhodesiense, the causative agent of African sleeping sickness. However, inheriting two APOL1 risk alleles significantly increases an individual's susceptibility to APOL1-mediated kidney disease.
What each genotype means
Typical APOL1 profile
This genotype represents the absence of the G2 risk variant at this specific position. It is considered the common or reference state in populations worldwide. Having this genotype does not confer the specific kidney disease risk associated with the G2 deletion.
This is the most common genotype globally, found in the vast majority of individuals across all ancestral groups.
Single copy carrier
You carry one copy of the G2 deletion variant and one copy of the common allele. Research indicates that APOL1-related kidney disease risk is primarily recessive, meaning individuals with only one risk allele typically do not have the same elevated risk as those with two copies. You should discuss your overall genetic health profile with a clinician.
This genotype is found at varying frequencies in populations of sub-Saharan African ancestry, where the G2 allele is more prevalent.
Increased kidney disease risk
This genotype indicates you carry two copies of the G2 deletion variant, which is associated with an increased risk of chronic kidney disease. While this risk is significant, it is important to note that the majority of people with two risk alleles do not develop kidney disease. You should consult with a healthcare provider to discuss kidney health monitoring and lifestyle factors.
This genotype is most common in individuals of recent sub-Saharan African ancestry and is rare in other global populations.
Molecular Anatomy of rs73284431
The rs73284431 variant represents a 6-base-pair in-frame deletion in exon 7 of the apolipoprotein L1 (APOL1) gene, mapped to chromosome 22q12.3. Specifically, this mutation causes the deletion of two amino acids, asparagine and tyrosine at codons 388 and 389 (often designated p.Asn388_Tyr389del or p.N388_Y389del). In biomedical literature, this specific deletion defines the APOL1 'G2' allele, distinguishing it from the wild-type 'G0' allele and the missense-defined 'G1' allele (comprising p.S342G and p.I384M). The affected region sits in the carboxy-terminal serum resistance-associated (SRA)-interacting coiled-coil domain of the ApoL1 protein. ApoL1 is normally an amphipathic serum protein bound to high-density lipoprotein particles. Because this six-nucleotide deletion directly disrupts the SRA-binding domain, it significantly alters how the ApoL1 protein folds, binds partner molecules, and integrates into cellular membranes.
Evolutionary Selection and Trypanolytic Protection
Human APOL1 is an integral component of the innate immune system that confers protection against African trypanosomiasis, or African sleeping sickness. The standard parasite Trypanosoma brucei brucei is eliminated by normal circulating ApoL1 (the G0 form), which penetrates the parasite's endosomes and induces lethal pore formation. However, a subspecies termed Trypanosoma brucei rhodesiense evolved a serum resistance-associated protein that neutralizes G0 ApoL1, allowing lethal infection in humans. Through positive natural selection occurring within the last 5,000 to 10,000 years in sub-Saharan Africa, the G2 deletion (rs73284431) emerged. The loss of residues N388 and Y389 impairs binding to the parasite's SRA protein, allowing ApoL1 to retain its trypanolytic ability against T. b. rhodesiense. Consequently, individuals carrying even one copy of the G2 allele acquired a critical survival advantage in regions where rhodesiense sleeping sickness was endemic.
Recessive Kidney Disease Associations
While rs73284431 offered an evolutionary advantage against parasitic infections, it exerts a damaging, gain-of-function effect on human renal tissue. Nephrology research demonstrates that APOL1-mediated kidney disease (AMKD) typically follows an autosomal recessive pattern of inheritance. Carrying a single G2 allele alongside a G0 reference allele generally does not cause overt renal damage. However, carrying two risk alleles—either homozygous G2/G2 or compound heterozygous G1/G2—substantially elevates the lifetime risk for focal segmental glomerulosclerosis (FSGS), hypertension-attributed end-stage kidney disease (ESKD), and HIV-associated nephropathy (HIVAN). Animal and cell models show that expressing the G2 risk protein disrupts podocyte endosomal trafficking, blocks autophagic flux, and damages mitochondrial membranes under inflammatory stress, ultimately triggering podocyte death and progressive glomerular scarring.
Population Frequency and Demographics
Because rs73284431 arose under localized pathogen pressure in Africa, its frequency tracks closely with sub-Saharan African ancestry rather than modern racial constructs. In western and central sub-Saharan African populations, the G2 allele frequency ranges roughly between 10% and 15%, while the companion G1 allele is often found at 20% to 25%. In self-identified African Americans, who possess substantial west African admixture, the G2 allele frequency sits near 15%, and approximately 13% of the overall population carries two APOL1 risk alleles (G1/G1, G1/G2, or G2/G2). In stark contrast, rs73284431 is virtually absent in populations lacking recent sub-Saharan African ancestry; allele frequencies in European, East Asian, and Indigenous American cohorts typically measure below 0.01% (less than 1 in 10,000 alleles).
Clinical Perspective: Actionability and Limitations
Possessing a high-risk APOL1 genotype containing the rs73284431 deletion is not a direct diagnosis of kidney disease. AMKD exhibits incomplete penetrance: the majority of individuals who possess two APOL1 risk alleles will never develop overt kidney failure or clinical nephropathy during their lifetime. Current clinical consensus views these variants as major genetic susceptibility factors that typically require a secondary 'second hit'—such as interferon release, systemic infection, poorly controlled hypertension, or environmental stressors—to initiate renal damage. Routine population-wide screening for rs73284431 is not currently standard, though genetic testing is frequently evaluated in potential living kidney donors and patients with unexplained nephrotic syndrome. Patients carrying G2 alleles can proactively optimize cardiovascular health, manage blood pressure, and monitor urine albumin with a healthcare professional.
How common is this variant?
The rs73284431 (G2) allele is found at frequencies of approximately 10% to 15% in individuals of sub-Saharan African ancestry (and around 15% among African Americans), while remaining exceedingly rare (<0.01%) in European and East Asian ancestral groups.
Frequently asked questions
What does the rs73284431 variant in APOL1 mean?
The rs73284431 variant is a 6-nucleotide deletion defining the APOL1 G2 allele. It evolved in sub-Saharan Africa to protect against parasitic sleeping sickness, but when paired with another risk allele, it raises the statistical risk of kidney disease.
Does having the APOL1 G2 allele mean I will develop kidney disease?
No, carrying the G2 allele does not guarantee kidney disease. APOL1-associated kidney disorders have incomplete penetrance, meaning most individuals with high-risk genotypes never develop severe kidney dysfunction, often requiring an additional environmental or inflammatory trigger.
What is the difference between APOL1 G1 and G2 alleles?
Both G1 and G2 are natural APOL1 variants that evolved to fight distinct trypanosome parasites and both confer kidney disease risk in a two-allele model. G1 consists of two amino acid substitutions, whereas G2 (rs73284431) is an in-frame deletion of two amino acids.
Is APOL1 rs73284431 kidney disease dominant or recessive?
Kidney disease risk associated with APOL1 rs73284431 is inherited in an autosomal recessive fashion. Having a single copy of G2 generally does not increase kidney risk unless it is inherited alongside a second risk allele, such as another G2 or a G1 allele.
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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A variant in the APOL1 gene (G1 risk allele) associated with chronic kidney disease in individuals of African ancestry.
Essential component of the African ancestry-specific APOL1 G1 risk haplotype associated with protection against sleeping sickness and elevated susceptibility to end-stage renal disease.
Known as the G1 risk allele, this variant significantly increases the risk of chronic kidney disease, especially in those with African ancestry.