Steroid-resistant nephrotic syndrome: genes and variants

Genes linked to Steroid-resistant 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.

  8 disease-causing and 8 uncertain variants in NPHS2 are linked to Steroid-resistant 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 Steroid-resistant nephrotic syndrome.

Weakly linked (only a few uncertain records): APOL1, COL4A3, COL4A4 and GLA.

Known disease-causing variants in Steroid-resistant nephrotic syndrome

Uncertain variants in Steroid-resistant nephrotic syndrome that look disease-causing

Which prediction tools work for Steroid-resistant nephrotic syndrome

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

• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 96 out of 100
• phyloP: 93 out of 100
• SIFT: 89 out of 100
• PolyPhen-2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Nephrotic syndrome is also caused by NPHS2 variants; they fall mostly in different places as the Steroid-resistant nephrotic syndrome variants (30 disease-causing).
• Idiopathic nephrotic syndrome is also caused by NPHS2 variants; they fall partly in the same places as the Steroid-resistant nephrotic syndrome variants (5 disease-causing).
• X-linked Alport syndrome is also caused by COL4A5 variants; they fall mostly in different places as the Steroid-resistant nephrotic syndrome variants (341 disease-causing).
• Alport syndrome is also caused by COL4A5 variants; they fall mostly in different places as the Steroid-resistant nephrotic syndrome variants (14 disease-causing).

Diseases related to Steroid-resistant nephrotic syndrome

• Nephrotic syndrome, also linked to COL4A5 and NPHS2
• X-linked Alport syndrome, also linked to COL4A5
• Alport syndrome, also linked to COL4A5
• Autosomal dominant Alport syndrome, also linked to COL4A5
• Rare genetic deafness, also linked to COL4A5
• Finnish congenital nephrotic syndrome, also linked to NPHS2
• Monogenic hearing loss, also linked to COL4A5
• Isolated macular dystrophy, also linked to COL4A5
• Idiopathic nephrotic syndrome, also linked to NPHS2
• Kidney disorder, also linked to COL4A5
• Focal segmental glomerulosclerosis, also linked to NPHS2
• Chronic kidney disease, also linked to COL4A5

Frequently asked questions

Which genes are linked to Steroid-resistant nephrotic syndrome?

In CATVariant, Steroid-resistant nephrotic syndrome is linked to 2 analyzed proteins: NPHS2 (Podocin) and COL4A5 (Collagen alpha-5(IV) chain).

How many genetic variants are linked to Steroid-resistant nephrotic syndrome?

31 variants: 9 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 11 are of uncertain significance or have conflicting reports.

Which uncertain variants in Steroid-resistant nephrotic syndrome look disease-causing?

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

Which variant effect predictor works best for Steroid-resistant nephrotic syndrome?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.96, based on 8 disease-causing and 199 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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