Focal segmental glomerulosclerosis: genes and variants

Genes linked to Focal segmental glomerulosclerosis

• 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.

  2 disease-causing and 13 uncertain variants in NPHS1 are linked to Focal segmental glomerulosclerosis.

• 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 Focal segmental glomerulosclerosis.

• 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.

  1 disease-causing and 1 uncertain variants in NPHS2 are linked to Focal segmental glomerulosclerosis.

• APOL1: Apolipoprotein L1

  It contributes to innate immunity and can form membrane pores that kill certain trypanosomes. The G1 and G2 risk variants provide protection against some African trypanosomes but markedly increase susceptibility to several forms of kidney disease in individuals carrying two risk alleles.

  0 disease-causing and 9 uncertain variants in APOL1 are linked to Focal segmental glomerulosclerosis.

Weakly linked (only a few uncertain records): DDX41, FAT1 and ITGB4.

Known disease-causing variants in Focal segmental glomerulosclerosis

Same protein, different disease

• Finnish congenital nephrotic syndrome is also caused by NPHS1 variants; they fall mostly in different places as the Focal segmental glomerulosclerosis variants (70 disease-causing).
• Nephrotic syndrome is also caused by NPHS1 variants; they fall mostly in different places as the Focal segmental glomerulosclerosis variants (4 disease-causing).
• Nephrotic syndrome is also caused by NPHS2 variants; they fall mostly in different places as the Focal segmental glomerulosclerosis variants (30 disease-causing).
• Steroid-resistant nephrotic syndrome is also caused by NPHS2 variants; they fall mostly in different places as the Focal segmental glomerulosclerosis variants (8 disease-causing).
• Idiopathic nephrotic syndrome is also caused by NPHS2 variants; they fall mostly in different places as the Focal segmental glomerulosclerosis variants (5 disease-causing).
• Autosomal recessive Alport syndrome is also caused by COL4A4 variants; they fall mostly in different places as the Focal segmental glomerulosclerosis variants (99 disease-causing).
• Alport syndrome is also caused by COL4A4 variants; they fall mostly in different places as the Focal segmental glomerulosclerosis variants (57 disease-causing).
• Hematuria, benign familial is also caused by COL4A4 variants; they fall mostly in different places as the Focal segmental glomerulosclerosis variants (51 disease-causing).
• Benign familial hematuria is also caused by COL4A4 variants; they fall mostly in different places as the Focal segmental glomerulosclerosis variants (17 disease-causing).
• Autosomal dominant Alport syndrome is also caused by COL4A4 variants; they fall mostly in different places as the Focal segmental glomerulosclerosis variants (6 disease-causing).

Diseases related to Focal segmental glomerulosclerosis

• Nephrotic syndrome, also linked to COL4A4, NPHS1 and NPHS2
• Finnish congenital nephrotic syndrome, also linked to NPHS1 and NPHS2
• Kidney disorder, also linked to APOL1 and NPHS1
• Alport syndrome, also linked to COL4A4
• Autosomal dominant Alport syndrome, also linked to COL4A4
• Autosomal recessive Alport syndrome, also linked to COL4A4
• Hematuria, benign familial, also linked to COL4A4
• Benign familial hematuria, also linked to COL4A4
• Steroid-resistant nephrotic syndrome, also linked to NPHS2
• Polycystic kidney disease, also linked to COL4A4
• Idiopathic nephrotic syndrome, also linked to NPHS2
• Chronic kidney disease, also linked to APOL1

Frequently asked questions

Which genes are linked to Focal segmental glomerulosclerosis?

In CATVariant, Focal segmental glomerulosclerosis is linked to 4 analyzed proteins: NPHS1 (Nephrin), COL4A4 (Collagen alpha-4(IV) chain), NPHS2 (Podocin) and APOL1 (Apolipoprotein L1).

How many genetic variants are linked to Focal segmental glomerulosclerosis?

33 variants: 4 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 25 are of uncertain significance or have conflicting reports.

Which uncertain variants in Focal segmental glomerulosclerosis look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

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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