What you carry at this position in your DNA and what research says about it.
Kidney Disease Risk: 7/10 evidence, 6 publications.
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Sample genotype (not yours): C/C
Typical Kidney Disease Risk
Two copies of the common allele are present, avoiding the podocin-related kidney risk. There is a very slight increase in gout susceptibility.
What this genotype means: Typical podocin protein structure; No elevated risk of adult-onset FSGS; Slightly higher baseline gout risk.
Sample genotype (not yours): C/T
Slightly Elevated Kidney Risk
One copy of the R229Q variant is present, which can elevate kidney disease risk if a second mutation is inherited. Diastolic blood pressure is slightly higher.
What this genotype means: Altered podocin-nephrin binding; Potential risk of late-onset FSGS if paired with another mutation; Slightly higher diastolic blood pressure.
Sample genotype (not yours): T/T
Two copies of the R229Q variant are present. While homozygous R229Q does not cause classic kidney disease on its own, blood pressure is slightly elevated.
What this genotype means: Moderately decreased podocin-nephrin binding; Slightly higher diastolic blood pressure; Slightly lower risk of gout.
Gene function and biological role
Gene Function: The NPHS2 gene encodes podocin, a membrane-anchored protein that is localized exclusively to the specialized slit diaphragms of kidney podocytes. Podocin plays a critical structural and functional role in maintaining the glomerular filtration barrier, which filters waste from the blood while retaining essential proteins. Mutations in this gene are the most common cause of childhood-onset autosomal recessive steroid-resistant nephrotic syndrome. When podocin is structurally altered, the filtration barrier fails, leading to severe protein leakage into the urine and progressive kidney damage. Understanding variations in this gene helps identify individuals at risk for atypical or late-onset glomerular diseases [1].
Variant Impact: The rs61747728 variant, also known as p.Arg229Gln or R229Q, is a missense mutation in the NPHS2 gene that changes the amino acid arginine to glutamine at position 229 of the podocin protein. This specific amino acid substitution alters the C-terminal dimerization of podocin, reducing its ability to bind to nephrin, another essential filtration barrier protein. Interestingly, this variant exhibits a unique mutation-dependent pathogenicity, meaning it does not cause disease on its own but becomes pathogenic when paired with specific other mutations on the opposite chromosome. It is relatively common in populations of European and South Asian ancestry [2]. Research has also linked this genetic variation to subtle systemic differences, including blood pressure regulation [1].
Key Insight: The R229Q variant is famous in genetics because it is only harmful when paired with specific other mutations on the opposite chromosome, making it a classic example of mutation-dependent pathogenicity.
Location: NPHS2. Chromosome 1 · 1q25.2 · 179.6 Mb
Estimated prevalence by population
Global 94.6%; European 92.7%; African 98.8%; East Asian 99.9%; South Asian 94.4%; Americas 96.3%; Ashkenazi 89.0%; Finnish 87.2%; Middle Eastern 99.3%; Amish 87.3%.
Estimated CC genotype frequency.
Global 5.3%; European 7.2%; African 1.2%; East Asian 0.1%; South Asian 5.5%; Americas 3.7%; Ashkenazi 10.7%; Finnish 12.4%; Middle Eastern 0.7%; Amish 12.3%.
Estimated CT genotype frequency.
Global 0.1%; European 0.1%; African < 0.1%; East Asian < 0.1%; South Asian 0.1%; Americas < 0.1%; Ashkenazi 0.3%; Finnish 0.4%; Middle Eastern < 0.1%; Amish 0.4%.
Estimated TT genotype frequency.
Showing effects for C/C genotype
Organ Systems
Kidney Function & Disease
Kidney Disease. Evidence: 6/10. Typical Risk.
Cardiovascular & Metabolic
Hypertension
Diastolic Blood Pressure. Evidence: 7/10. Source: PMID 33230300. Typical.
Gout & Uric Acid
Gout. Evidence: 7/10. Source: PMID 39406924. ~1.1x Higher Risk.
Immunity & Inflammation
Inflammatory & Circulating Protein Markers
Glycoprotein Acetyls. Evidence: 7/10. Source: PMID 41044249. Typical.
Showing effects for C/T genotype
Kidney Disease. Evidence: 6/10. Slightly Elevated.
Diastolic Blood Pressure. Evidence: 7/10. Source: PMID 33230300. +0.25 mmHg.
Gout. Evidence: 7/10. Source: PMID 39406924. Typical.
Glycoprotein Acetyls. Evidence: 7/10. Source: PMID 41044249. +0.04 mmol/L.
Showing effects for T/T genotype
Diastolic Blood Pressure. Evidence: 7/10. Source: PMID 33230300. +0.50 mmHg.
Gout. Evidence: 7/10. Source: PMID 39406924. Slightly Lower Risk.
Glycoprotein Acetyls. Evidence: 7/10. Source: PMID 41044249. +0.08 mmol/L.
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Glomerular filtration functions normally under typical conditions because the podocin protein retains its standard arginine residue at position 229. This homozygous reference state avoids the structural alterations that can compromise the kidney's filtration barrier. Consequently, there is no elevated risk for adult-onset steroid-resistant nephrotic syndrome or focal segmental glomerulosclerosis from this locus. However, large-scale genetic mapping studies show a minor, 1.1-fold increase in the odds of developing gout associated with this common genotype [1]. Blood pressure regulation and systemic inflammatory markers like glycoprotein acetyls remain at baseline levels [2]. No special clinical monitoring or kidney-related genetic precautions are typically indicated for this genetic profile.
Typical podocin protein structure; No elevated risk of adult-onset FSGS; Slightly higher baseline gout risk.
Sample genotype: CT (Heterozygous)
Heterozygosity for the R229Q variant introduces one copy of the altered podocin protein, which has a reduced binding affinity for nephrin. On its own, carrying a single copy of this variant does not cause kidney disease. However, if a second pathogenic mutation is present on the other NPHS2 allele, particularly in exons 7 or 8, it can trigger late-onset steroid-resistant nephrotic syndrome or focal segmental glomerulosclerosis. This compound heterozygous state causes the altered proteins to mislocalize within the kidney's filtration barrier. Additionally, large-scale association studies link this genotype to a minor increase of approximately 0.25 mmHg in diastolic blood pressure [1]. Systemic levels of glycoprotein acetyls, a marker of inflammation, are also slightly elevated [2].
Altered podocin-nephrin binding; Potential risk of late-onset FSGS if paired with another mutation; Slightly higher diastolic blood pressure.
Sample genotype: TT (Homozygous)
Homozygosity for the R229Q variant means all produced podocin proteins carry the glutamine substitution, which moderately decreases nephrin binding. Surprisingly, clinical studies show that having two copies of R229Q does not cause steroid-resistant nephrotic syndrome or focal segmental glomerulosclerosis on its own. The severe disease phenotype requires a dominant-negative interaction with a different, specific mutation on the opposite chromosome, which is absent here. Nevertheless, this genotype is associated with a modest increase of about 0.50 mmHg in diastolic blood pressure [1]. Systemic inflammatory markers, specifically glycoprotein acetyls, are also slightly higher than in the general population [2]. Conversely, this profile is associated with a slightly lower risk of developing gout [3].
Moderately decreased podocin-nephrin binding; Slightly higher diastolic blood pressure; Slightly lower risk of gout.
Variants with shared genetic architecture
rs10857147 · FGF5 Gene · Chr 4 · Blood Pressure
rs11191580 · NT5C2 Gene · Chr 10 · Blood Pressure and Brain
rs11222084 · ZBTB44-DT Gene · Chr 11 · Blood Pressure Profile
Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration.
A genome-wide association analysis reveals new pathogenic pathways in gout.
A genetic map of human metabolism across the allele frequency spectrum.
Content updated August 2026.
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