rs60910145 — APOL1 G1 I384M

Second component of the APOL1 G1 kidney disease risk haplotype — a missense variant that, together with rs73885319 (S342G), confers 7- to 29-fold increased risk for non-diabetic CKD under a recessive inheritance model in African-ancestry populations

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APOL1 G1 I384M — Half of the Kidney Disease Risk Haplotype That Shaped Human Evolution

Apolipoprotein L1 (APOL1) is a secreted protein that circulates on HDL particles11 secreted protein that circulates on HDL particles
APOL1 is the only human apolipoprotein with trypanolytic activity — it kills African trypanosomes by forming ion channels in their lysosomal membranes and serves as the innate immune system's weapon against Trypanosoma brucei, the parasite causing African sleeping sickness. The G1 risk haplotype consists of two missense variants in near-perfect linkage disequilibrium: rs73885319 (S342G) and rs60910145 (I384M). Both sit within the SRA-interacting domain22 SRA-interacting domain
Serum Resistance-Associated protein (SRA) is expressed by the human-infective subspecies T.b. rhodesiense; it binds and neutralizes wild-type APOL1 of the APOL1 protein, and together they alter the protein's ability to be neutralized by the parasite — conferring resistance to sleeping sickness but, under a recessive model, dramatically increasing kidney disease risk.

The Mechanism

The I384M substitution (isoleucine to methionine at position 384) occurs in the C-terminal region of the SRA-binding domain. While functional studies show that the S342G component drives the trypanolytic gain-of-function33 functional studies show that the S342G component drives the trypanolytic gain-of-function
Cooper et al. 2017 demonstrated that S342G alone confers trypanosome resistance in vivo, while I384M alone does not, both variants are inherited together as the G1 haplotype and are required for the full kidney disease risk phenotype. The APOL1 risk variants cause kidney injury through multiple mechanisms: they form active cation channels at the plasma membrane44 active cation channels at the plasma membrane
Risk-variant APOL1 inserts into podocyte membranes, creating ion pores that disrupt cellular homeostasis of kidney podocytes, induce mitochondrial dysfunction, and trigger endoplasmic reticulum stress. Crucially, disease requires a recessive model — two risk alleles55 recessive model — two risk alleles
G1/G1, G2/G2, or G1/G2 compound heterozygosity; carriers of a single risk allele have minimal kidney risk — meaning one copy is protective against trypanosomes without causing kidney harm, while two copies cross a threshold into cytotoxicity.

The Evidence

The landmark 2010 discovery66 landmark 2010 discovery
Genovese et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science, 2010 identified the G1 and G2 haplotypes as the genetic explanation for the 3- to 5-fold excess kidney disease burden in African Americans. Two-risk-allele carriers face dramatically elevated odds: OR 17 for FSGS, OR 29 for HIV-associated nephropathy (HIVAN), and OR 7–10 for hypertension-attributed end-stage renal disease77 OR 17 for FSGS, OR 29 for HIV-associated nephropathy (HIVAN), and OR 7–10 for hypertension-attributed end-stage renal disease
Kopp et al. JASN, 2011. The AASK and CRIC cohort study88 AASK and CRIC cohort study
Parsa et al. APOL1 risk variants, race, and progression of chronic kidney disease. NEJM, 2013 confirmed that the high-risk genotype independently accelerates CKD progression (HR 1.88 for composite renal endpoints), regardless of baseline kidney function.

However, penetrance is incomplete — approximately 15–20% of two-risk-allele carriers develop clinical kidney disease, indicating that "second hits" are required99 "second hits" are required
Known triggers include HIV infection, interferon signalling (e.g. from COVID-19 or lupus), and hypertension — each upregulates APOL1 expression in podocytes. This means the genotype creates susceptibility, not certainty. A targeted therapy, inaxaplin, reduced proteinuria by 47.6%1010 inaxaplin, reduced proteinuria by 47.6%
Phase 2a trial: 13 weeks of inaxaplin in patients with two APOL1 risk alleles and biopsy-proven FSGS in a phase 2a trial of APOL1-associated FSGS, marking the first genotype-directed kidney disease treatment.

Population Context

The G1 haplotype is found almost exclusively in people of African ancestry — approximately 22% allele frequency in African and African American populations, compared to less than 0.01% in Europeans and East Asians. This extreme population stratification reflects positive selection driven by trypanosome resistance1111 positive selection driven by trypanosome resistance
The G1 and G2 variants rose to high frequency in West Africa because heterozygous carriers were protected against T.b. rhodesiense sleeping sickness — a classic example of balancing selection similar to sickle cell trait and malaria. Among African Americans, approximately 13% carry two APOL1 risk alleles (G1/G1, G2/G2, or G1/G2), placing them in the high-risk category.

Practical Implications

For carriers of a single G1 allele (GT genotype), the clinical consequence is minimal for kidney health and may offer innate immunity benefits against trypanosome infection. For two-risk-allele carriers (requiring knowledge of both APOL1 risk variant loci — G1 and G2), the imperative is early and sustained kidney monitoring to detect subclinical disease before irreversible nephron loss. Blood pressure control is critical because hypertension acts as a "second hit" that accelerates APOL1-mediated podocyte injury.

Interactions

Rs60910145 is in near-perfect linkage disequilibrium with rs73885319 — together they define the G1 haplotype. The kidney disease risk requires two APOL1 risk alleles in any combination: G1/G1 homozygosity, G2/G2 homozygosity (rs71785313), or G1/G2 compound heterozygosity. A compound action covering the G1+G2 interaction would be appropriate for users carrying risk alleles at both loci. The recently discovered N264K modifier variant (rs73015316) substantially reduces penetrance when co-inherited with G2-containing haplotypes — an important consideration for future genotyping completeness.

Genotype Interpretations

What each possible genotype means for this variant.

TT Reference Genotype Normal

No APOL1 G1 I384M variant — standard APOL1 function at this position

You carry two copies of the reference T allele (isoleucine at position 384). You do not have the I384M component of the APOL1 G1 risk haplotype. This is the genotype found in approximately 87% of the global population and in virtually all people of non-African ancestry. Your kidney disease risk is not elevated by this variant.

GG G1 I384M Homozygous High Risk

Two copies of the APOL1 G1 I384M variant — component of the high-risk genotype for CKD, FSGS, and HIVAN

The GG genotype at rs60910145, combined with near-certain homozygosity for rs73885319 (S342G), places you in the APOL1 high-risk category. The landmark studies from Genovese (2010) and Kopp (2011) established odds ratios of 17 for focal segmental glomerulosclerosis (FSGS), 29 for HIV-associated nephropathy, and 7–10 for hypertension-attributed end-stage renal disease. The Parsa et al. NEJM 2013 study demonstrated an independent hazard ratio of 1.88 for composite renal endpoints in CKD patients with two risk alleles.

The mechanism involves APOL1 risk-variant protein forming cation channels in podocyte plasma membranes, leading to ion flux disruption, mitochondrial dysfunction, and endoplasmic reticulum stress. Disease manifestation typically requires a "second hit" — HIV infection (50% of high-risk carriers developed HIVAN before effective antiretroviral therapy), interferon signalling from viral infections or autoimmune disease (including COVID-19-associated collapsing glomerulopathy), or sustained hypertension.

An important therapeutic development: inaxaplin, a small-molecule APOL1 inhibitor, demonstrated a 47.6% reduction in proteinuria over 13 weeks in a phase 2a trial of APOL1-associated FSGS patients. This is the first genotype-directed kidney therapy and is advancing through clinical trials.

GT G1 I384M Carrier Carrier

One copy of the APOL1 G1 I384M variant — minimal kidney risk as a single carrier

The I384M variant is the second of two missense changes that define the APOL1 G1 haplotype (the first being S342G at rs73885319). These two variants are in near-perfect linkage disequilibrium — if you carry I384M, you almost certainly also carry S342G on the same chromosome. However, disease risk requires two APOL1 risk alleles (G1/G1, G2/G2, or G1/G2), not just one. Large cohort studies including the AASK and CRIC trials show that heterozygous carriers have kidney function trajectories similar to non-carriers. The evolutionary advantage of carrying one copy — resistance to African trypanosomes — likely explains why the G1 allele reached 22% frequency in West African populations despite the recessive kidney disease risk.