Nephrotic syndrome: genes and variants

Genes linked to Nephrotic syndrome

• NPHS2: Podocin

  It organizes nephrin-containing slit-diaphragm complexes in podocytes and helps maintain the glomerular filtration barrier. Biallelic pathogenic variants are a major cause of steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis.

  30 disease-causing and 59 uncertain variants in NPHS2 are linked to Nephrotic syndrome.

• NPHS1: Nephrin

  It forms a key structural and signaling component of the slit diaphragm between glomerular podocyte foot processes. Biallelic loss-of-function variants cause congenital nephrotic syndrome of the Finnish type with massive protein loss beginning early in life.

  4 disease-causing and 53 uncertain variants in NPHS1 are linked to Nephrotic syndrome.

• WT1: Wilms tumor protein

  It controls transcriptional programs required for kidney and gonadal development and also restrains or promotes cell growth in a context-dependent manner. Germline pathogenic variants cause Wilms-tumor predisposition and Denys-Drash or Frasier syndromes, while somatic alterations occur in some leukemias.

  1 disease-causing and 1 uncertain variants in WT1 are linked to Nephrotic syndrome.

• NOS1AP: Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein

  It regulates neuronal nitric-oxide signaling and interacts with proteins that influence cardiac repolarization and synaptic function. Common variants near the locus are reproducibly associated with QT-interval duration, but large-effect monogenic disease from NOS1AP variants is not well established.

  1 disease-causing and 1 uncertain variants in NOS1AP are linked to Nephrotic syndrome.

• NR3C1: Glucocorticoid receptor

  It converts glucocorticoid binding into transcriptional programs that regulate metabolism, stress responses, inflammation, and immune activity. Loss-of-function variants can cause glucocorticoid resistance, while excessive or prolonged signaling underlies many adverse effects of corticosteroid therapy.

  0 disease-causing and 0 uncertain variants in NR3C1 are linked to Nephrotic syndrome.

• SLC12A1: Solute carrier family 12 member 1

  It reabsorbs sodium, potassium, and chloride in the thick ascending limb of the kidney, helping generate the medullary concentration gradient and maintain salt balance. Biallelic loss-of-function variants cause Bartter syndrome type 1 with renal salt wasting.

  0 disease-causing and 0 uncertain variants in SLC12A1 are linked to Nephrotic syndrome.

• SLC12A3: Solute carrier family 12 member 3

  It reabsorbs sodium and chloride in the distal convoluted tubule and is a major determinant of renal salt and magnesium handling. Biallelic loss-of-function variants cause Gitelman syndrome with hypokalemic metabolic alkalosis, hypomagnesemia, and low urinary calcium.

  0 disease-causing and 0 uncertain variants in SLC12A3 are linked to Nephrotic syndrome.

• FAT1: Protocadherin Fat 1

  4 disease-causing and 1 uncertain variants in FAT1 are linked to Nephrotic syndrome.

• COL4A4: Collagen alpha-4(IV) chain

  It combines with the alpha3 and alpha5 chains to form the mature type IV collagen network of glomerular, cochlear, and ocular basement membranes. Pathogenic variants cause autosomal Alport-spectrum disease and can present with isolated persistent hematuria.

  1 disease-causing and 0 uncertain variants in COL4A4 are linked to Nephrotic syndrome.

• COL4A5: Collagen alpha-5(IV) chain

  It is essential for the alpha3-alpha4-alpha5 type IV collagen network that gives glomerular and cochlear basement membranes their mature mechanical properties. Pathogenic variants cause X-linked Alport syndrome, with progressive kidney disease, hearing loss, and characteristic ocular findings.

  1 disease-causing and 0 uncertain variants in COL4A5 are linked to Nephrotic syndrome.

Weakly linked (only a few uncertain records): CLCN5.

Known disease-causing variants in Nephrotic syndrome

Uncertain variants in Nephrotic syndrome that look disease-causing

Which prediction tools work for Nephrotic syndrome

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 92 out of 100
• EVE: 90 out of 100
• REVEL: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 90 out of 100
• PolyPhen-2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 86 out of 100
• MetaLR: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 81 out of 100

Same protein, different disease

• Finnish congenital nephrotic syndrome is also caused by NPHS1 variants; they fall mostly in different places as the Nephrotic syndrome variants (70 disease-causing).
• X-linked Alport syndrome is also caused by COL4A5 variants; they fall mostly in different places as the Nephrotic syndrome variants (341 disease-causing).
• Alport syndrome is also caused by COL4A5 variants; they fall mostly in different places as the Nephrotic syndrome variants (14 disease-causing).
• Autosomal recessive Alport syndrome is also caused by COL4A4 variants; they fall mostly in different places as the Nephrotic syndrome variants (99 disease-causing).
• Alport syndrome is also caused by COL4A4 variants; they fall mostly in different places as the Nephrotic syndrome variants (57 disease-causing).
• Hematuria, benign familial is also caused by COL4A4 variants; they fall mostly in different places as the Nephrotic syndrome variants (51 disease-causing).
• Benign familial hematuria is also caused by COL4A4 variants; they fall mostly in different places as the Nephrotic syndrome variants (17 disease-causing).
• Autosomal dominant Alport syndrome is also caused by COL4A4 variants; they fall mostly in different places as the Nephrotic syndrome variants (6 disease-causing).
• Frasier syndrome is also caused by WT1 variants; they fall mostly in different places as the Nephrotic syndrome variants (6 disease-causing).
• Wilms tumor is also caused by WT1 variants; they fall mostly in different places as the Nephrotic syndrome variants (6 disease-causing).
• 11p partial monosomy syndrome is also caused by WT1 variants; they fall mostly in different places as the Nephrotic syndrome variants (5 disease-causing).

Diseases related to Nephrotic syndrome

• Kidney disorder, also linked to COL4A5, NPHS1, SLC12A1 and WT1
• Focal segmental glomerulosclerosis, also linked to COL4A4, NPHS1 and NPHS2
• Alport syndrome, also linked to COL4A4 and COL4A5
• Autosomal dominant Alport syndrome, also linked to COL4A4 and COL4A5
• Finnish congenital nephrotic syndrome, also linked to NPHS1 and NPHS2
• Steroid-resistant nephrotic syndrome, also linked to COL4A5 and NPHS2
• Bartter syndrome, also linked to SLC12A1 and SLC12A3
• Chronic kidney disease, also linked to COL4A5 and SLC12A3
• X-linked Alport syndrome, also linked to COL4A5
• Autosomal recessive Alport syndrome, also linked to COL4A4
• Familial hypokalemia-hypomagnesemia, also linked to SLC12A3
• Hematuria, benign familial, also linked to COL4A4

Frequently asked questions

Which genes are linked to Nephrotic syndrome?

In CATVariant, Nephrotic syndrome is linked to 10 analyzed proteins: NPHS2 (Podocin), NPHS1 (Nephrin), WT1 (Wilms tumor protein), NOS1AP (Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein), NR3C1 (Glucocorticoid receptor), SLC12A1 (Solute carrier family 12 member 1) and 4 more.

How many genetic variants are linked to Nephrotic syndrome?

201 variants: 42 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 115 are of uncertain significance or have conflicting reports.

Which uncertain variants in Nephrotic syndrome look disease-causing?

3 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example NPHS2 C124Y, NPHS2 R322P and NPHS2 P118S. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Nephrotic syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.92, based on 15 disease-causing and 38 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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