Discussion

We report a Chinese individual with biopsy-proven FSGS carrying a novel TRPC6 variant, c.131C>T p.(Pro44Leu), which is extremely rare in public databases (gnomAD allele frequency: 4.0 × 10−6). The predominance of benign predictions from most in silico tools, together with the lack of functional studies, supports its classification as a variant of uncertain significance. The patient achieved significant proteinuria reduction with supportive therapy alone, suggesting a mild disease trajectory. A recent large-scale study by Wooden et al. (Wooden et al., 2025) analyzing 64 patients from 39 families with TRPC6-associated podocytopathy identified 21 unique missense variants and defined three distinct protein regional hotspots, further supporting the clinical significance of variants in this gene and providing a valuable reference for interpreting novel variants such as p.Pro44Leu. Additionally, a Chinese pedigree study identified a gain-of-function TRPC6 Q134P variant in a late-onset FSGS family, demonstrating that functional alterations in TRPC6 can produce a mild, delayed phenotype (Liu et al., 2021). More recently, a Chinese cohort study of adult FSGS patients reported that genetic mutations were associated with better short-term kidney prognosis but no differences in long-term prognosis (Min et al., 2025). These observations highlight the importance of functional validation and population-specific reference data for interpreting TRPC6 variants across diverse ethnic groups. We acknowledge that a VUS should not guide clinical decisions alone. Here, the decision to avoid immunosuppression was phenotype-driven; the genetic finding was retrospective support. This practice is consistent with published guidance that a VUS should not be used alone for clinical decisions, while recognizing that genetic testing can still inform management when integrated with phenotype (Savige, 2024).

Based on the podocytopathy consensus (Romagnani et al., 2025), this patient’s phenotype (body mass index 20.58, no diabetes, no low birth weight) makes adaptive factors unlikely; autoimmune disease typically presents with nephrotic syndrome. Thus, genetic podocytopathy is consistent.

A practical diagnostic approach should consider genetic FSGS in patients presenting with onset under 30 years, family history of kidney disease, biopsy findings showing FSGS not otherwise specified, sub-nephrotic proteinuria, or lack of response to immunosuppressive therapy (Romagnani et al., 2025; Vriese et al., 2018). In such patients, early genetic testing can help distinguish monogenic forms from primary FSGS, thereby avoiding unnecessary courses of corticosteroids or calcineurin inhibitors, which carry substantial side effects. Even in resource-limited settings where genetic testing is not immediately accessible, the clinical phenotype alone may justify a trial of supportive therapy before initiating immunosuppression. Our patient exemplifies this approach: supportive care was initiated upfront; genetic testing later provided supportive evidence and reinforced this strategy. RAS inhibition combined with dapagliflozin improves hyperfiltration in remnant nephrons through both hemodynamic and non-hemodynamic mechanisms, with robust evidence supporting their use in CKD, including patients with FSGS lesions (Wheeler et al., 2022). Endothelin receptor antagonists have demonstrated antiproteinuric effects in chronic kidney disease. In IgA nephropathy and Alport syndrome, a hereditary glomerular disease that can present with FSGS-like lesions, selective endothelin A receptor antagonists including atrasentan and ambrisentan have shown significant proteinuria reduction with preserved kidney function (Song et al., 2024; Shi et al., 2025). Mechanistically, endothelin A receptor blockade attenuates glomerular endothelial injury, reduces mesangial proliferation, and modulates profibrotic pathways such as AKT/GSK-3β signaling (Bhadange and Gaikwad, 2026). Although sparsentan, a dual endothelin-angiotensin receptor antagonist, showed superior proteinuria reduction in FSGS compared to irbesartan (Rheault et al., 2023), it remains unavailable in China. Given the established renoprotective effects of RAS inhibition, SGLT-2 inhibition, and endothelin receptor antagonists in proteinuric glomerular diseases, including genetic kidney diseases that exhibit FSGS lesions, we applied this evidence to our patient by adding ambrisentan to the supportive regimen.

The p.Pro44Leu variant lies upstream of the first ankyrin repeat domain (residues 97–316), outside the classical FSGS mutation hotspot within the ankyrin repeats themselves. Its surface-exposed location—predicted to face outward from the channel core in the homotetrameric TRPC6 configuration—suggests involvement in protein-protein interactions rather than pore function. Together with the observed interaction network between TRPC6 and slit diaphragm proteins (NPHS2 and NPHS1) and literature reports of nephrin binding to the TRPC6 N-terminus (Kanda et al., 2011), we hypothesize that p.Pro44Leu alters local surface conformation, interfering with slit diaphragm protein interactions. Additionally, RNF24 regulates TRPC6 trafficking via the ankyrin repeat domain (Lussier et al., 2008); although Pro44 is upstream, it is plausible that this variant may affect ankyrin repeat domain conformation, disrupting RNF24-mediated regulation. However, this mechanistic interpretation remains hypothetical, and direct experimental evidence is needed to confirm pathogenicity.

The identification of a TRPC6 variant in this patient has immediate clinical implications and opens future therapeutic opportunities. An oral TRPC6 inhibitor (BI 764198) recently demonstrated a 35% proteinuria response rate in a phase 2 trial (Trachtman et al., 2026). For this patient and others with TRPC6-associated FSGS, genetic diagnosis not only enables avoidance of unnecessary immunosuppression but also may inform eligibility for emerging targeted therapies, should they become available. In regions where these agents are not yet accessible, genetic testing still offers value by informing prognosis, guiding family counseling, and supporting informed shared decision-making between clinicians and patients.

This report expands the variant spectrum of TRPC6-associated FSGS and provides a practical example of how genetic testing can directly inform clinical management in young patients with unexplained FSGS. The integration of genetic diagnosis into routine nephrology practice informs personalized therapeutic decision-making, minimizes unnecessary treatment-related harm, and facilitates patient eligibility for emerging targeted therapies. We advocate for early genetic testing in suspected monogenic FSGS to optimize patient outcomes and resource utilization.

Clinical takeaway

This case illustrates that structural modeling of novel variants can provide supportive insights that may inform clinical reasoning, even in the absence of functional studies. The surface-exposed, non-core location of p.Pro44Leu was consistent with the patient’s mild clinical phenotype. We suggest that structural prediction should be considered alongside clinical features in the interpretation of genetic variants in FSGS to guide risk stratification and therapeutic decision-making.