Polycystic kidney disease: genes and variants

Genes linked to Polycystic kidney disease

• PKD2: Polycystin-2

  It provides calcium-permeable polycystin channel activity and forms signaling complexes with polycystin-1 in renal epithelial cells. Loss-of-function variants cause autosomal dominant polycystic kidney disease, generally with a milder average course than PKD1-associated disease.

  7 disease-causing and 188 uncertain variants in PKD2 are linked to Polycystic kidney disease.

• PKD1: Polycystin-1

  Together with polycystin-2, it participates in tubular signaling, mechanosensation, and maintenance of renal epithelial architecture. Loss-of-function variants are the most common cause of autosomal dominant polycystic kidney disease.

  0 disease-causing and 36 uncertain variants in PKD1 are linked to Polycystic kidney disease.

• 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 Polycystic kidney disease.

Weakly linked (only a few uncertain records): PIK3CA and RAD51D.

Where Polycystic kidney disease variants cluster

• PKD2 Extracellular (positions 242–468): 6 of 7 disease-causing changes, 3.7× more than its size predicts.

Known disease-causing variants in Polycystic kidney disease

Which prediction tools work for Polycystic kidney disease

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

• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 93 out of 100

Same protein, different disease

• Autosomal dominant polycystic kidney disease is also caused by PKD2 variants; they fall mostly in different places as the Polycystic kidney disease variants (6 disease-causing).
• Autosomal recessive Alport syndrome is also caused by COL4A4 variants; they fall mostly in different places as the Polycystic kidney disease variants (99 disease-causing).
• Alport syndrome is also caused by COL4A4 variants; they fall mostly in different places as the Polycystic kidney disease variants (57 disease-causing).
• Hematuria, benign familial is also caused by COL4A4 variants; they fall mostly in different places as the Polycystic kidney disease variants (51 disease-causing).
• Benign familial hematuria is also caused by COL4A4 variants; they fall mostly in different places as the Polycystic kidney disease variants (17 disease-causing).
• Autosomal dominant Alport syndrome is also caused by COL4A4 variants; they fall mostly in different places as the Polycystic kidney disease variants (6 disease-causing).

Diseases related to Polycystic kidney disease

• Polycystic kidney disease, adult type, also linked to PKD1 and PKD2
• Autosomal dominant polycystic kidney disease, also linked to PKD1 and PKD2
• Kidney disorder, also linked to PKD1 and PKD2
• Meckel syndrome, also linked to PKD1 and PKD2
• Chronic kidney disease, also linked to PKD1 and PKD2
• 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
• Nephrotic syndrome, also linked to COL4A4
• Benign familial hematuria, also linked to COL4A4
• Focal segmental glomerulosclerosis, also linked to COL4A4

Frequently asked questions

Which genes are linked to Polycystic kidney disease?

In CATVariant, Polycystic kidney disease is linked to 3 analyzed proteins: PKD2 (Polycystin-2), PKD1 (Polycystin-1) and COL4A4 (Collagen alpha-4(IV) chain).

How many genetic variants are linked to Polycystic kidney disease?

288 variants: 8 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 225 are of uncertain significance or have conflicting reports.

Which uncertain variants in Polycystic kidney disease look disease-causing?

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

Which variant effect predictor works best for Polycystic kidney disease?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.93, based on 8 disease-causing and 206 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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