rs73885316 — APOL1 p.N264K

APOL1 p.N264K — The Protective Modifier That Cancels G2 Kidney Risk

The APOL1 gene encodes apolipoprotein L1¹¹ apolipoprotein L1
APOL1 is the human innate immune weapon against African trypanosomes; it forms ion channels in parasite membranes, killing them, a protein best known for its connection to chronic kidney disease in people of African ancestry. Two "risk haplotypes" — G1 and G2 — evolved to fight trypanosome parasites but cause focal segmental glomerulosclerosis (FSGS)²² focal segmental glomerulosclerosis (FSGS)
A kidney disease where the glomeruli — the tiny filtering units — become scarred, leading to protein in the urine and eventual kidney failure and related nephropathies when a person carries two risk alleles. Yet not all G2 carriers develop kidney disease. One key reason: the p.N264K variant (rs73885316, also called M1), a missense change that silences G2's cytotoxicity.

The Mechanism

The G1 and G2 risk variants cause kidney disease by making APOL1 toxic to podocytes³³ podocytes
The highly specialized kidney cells that wrap around glomerular capillaries to form the filtration barrier; podocytes do not regenerate if lost. The variant protein forms aberrant ion channels⁴⁴ ion channels
Pore-like structures that allow sodium, potassium, and calcium ions to flow across cell membranes, disrupting the normal electrochemical balance in podocyte membranes, depleting intracellular potassium and triggering cell death.

The p.N264K substitution — asparagine to lysine at position 264 — sits in the membrane-addressing domain of APOL1, adjacent to the pore-lining segment. In a 2026 structural study⁵⁵ 2026 structural study
Höffken et al. — The APOL1 variant p.N264K is predicted to block ion flow by occluding a pore at the cell surface. Life Sci Alliance, 2026, AlphaFold3 modeling and molecular dynamics simulations showed that the bulkier, positively charged lysine side chain at position 264 physically occludes the ion pore formed by the G2 protein. The M1-G2 protein retains normal cellular localization and surface expression but cannot conduct ions — the pore is blocked.

Critically, N264K and G1 are mutually exclusive⁶⁶ mutually exclusive
Carriers of G1 always have asparagine at position 264; the G1 haplotype physically cannot also carry N264K due to the evolutionary history of these alleles. This means N264K protects only against G2-containing risk genotypes (G1G2 and G2G2), not against G1G1.

The M1 allele likely originated on a non-risk G0 (wild-type) background. A 2025 haplotype study⁷⁷ 2025 haplotype study
Simeone et al. — APOL1 p.N264K is co-inherited with the G2 kidney disease risk variant through a proximity recombination event. G3 (Bethesda), 2025 found that M1 was incorporated into the G2 haplotype through an unusual recombination event within a very short 367-base-pair window between two strong recombination hotspots flanking APOL1 — an evolutionary quirk that created the protective M1-G2 haplotype.

The Evidence

The protective effect of N264K was quantified in a case-control study of 528 FSGS patients and 2,606 genetically matched controls⁸⁸ case-control study of 528 FSGS patients and 2,606 genetically matched controls
Gupta et al. — Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease. Nat Commun, 2023. Among individuals carrying G1G2 genotypes, the presence of N264K reduced the FSGS odds ratio to 0.136 — an 86% risk reduction. For G2G2 homozygotes, the OR was essentially 0, representing near-complete protection. The combined G1G2 + G2G2 group showed an overall OR of 0.08 with N264K present.

A large clinical cohort of 107,696 individuals confirmed these findings in a 2026 JAMA Network Open study⁹⁹ 2026 JAMA Network Open study
Martinelli et al. — Precision Diagnosis in APOL1 Kidney Disease With the p.N264K M1 Protective Variant. JAMA Netw Open, 2026. M1 was significantly inversely associated with FSGS and steroid-resistant nephrotic syndrome (SRNS) across APOL1 high-risk genotypes (OR 0.20, P = 3.69 × 10⁻³). M1 was four times more frequent in APOL1 high-risk individuals whose CKD had a different cause than in those with FSGS/SRNS, suggesting that M1 carriers with CKD likely have an alternative, potentially treatable underlying cause rather than APOL1-driven disease.

Practical Implications

For individuals of African ancestry who carry two APOL1 risk alleles (particularly G1G2 or G2G2 genotypes), testing for the N264K modifier is clinically important. A G2G2 or G1G2 individual who also carries N264K on the G2 chromosome has markedly lower kidney disease risk than a G2G2 individual without N264K. Conversely, a G1G2 or G2G2 individual without N264K faces substantially elevated risk and warrants active kidney monitoring.

For AC heterozygotes: you carry one copy of the N264K protective allele on one chromosome. If this A allele is co-inherited with a G2 allele on the same chromosome (in cis), it provides protection for that G2 copy. Understanding your full haplotype context — specifically whether the A allele is in cis with G2 — is necessary to interpret your kidney disease risk correctly.

For AA homozygotes (extremely rare in any population): both chromosomes carry the N264K allele. If either chromosome also carries G2, both G2 copies would be protected by the co-inherited N264K.

Interactions

The N264K modifier interacts directly with the APOL1 G2 variant (rs71785313 — the 6-bp deletion removing Asn388 and Tyr389). When N264K is on the same chromosome as G2 (in cis), it abolishes the cytotoxic effect. When N264K is on the opposite chromosome from G2 (in trans), it does not protect the G2 copy.

N264K has no known protective effect against the G1 haplotype variants (rs73885319 S342G and rs60910145 I384M). The G1 and N264K alleles are mutually exclusive — they cannot co-exist on the same chromosome due to their evolutionary history.

For individuals with APOL1 high-risk genotypes involving only G1 (G1G1 homozygotes), N264K status is irrelevant — their kidney risk remains elevated regardless of N264K results.