Alport syndrome: genes and variants

Genes linked to Alport syndrome

• COL4A3: Collagen alpha-3(IV) chain

  It contributes to the alpha3-alpha4-alpha5 type IV collagen network that forms the specialized basement membrane of the renal glomerulus, cochlea, and eye. Pathogenic variants cause Alport-spectrum disease and thin-basement-membrane nephropathy, with variable kidney and hearing involvement.

  128 disease-causing and 216 uncertain variants in COL4A3 are linked to Alport 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.

  57 disease-causing and 97 uncertain variants in COL4A4 are linked to Alport 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.

  14 disease-causing and 1 uncertain variants in COL4A5 are linked to Alport syndrome.

Weakly linked (only a few uncertain records): CLDN14.

Known disease-causing variants in Alport syndrome

Showing 60 of 199.

Uncertain variants in Alport syndrome that look disease-causing

Which prediction tools work for Alport syndrome

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

• REVEL: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 99 out of 100
• phyloP: 99 out of 100
• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 98 out of 100
• SIFT: 96 out of 100
• MutPred2: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 94 out of 100

Same protein, different disease

• Autosomal dominant Alport syndrome is also caused by COL4A3 variants; they fall partly in the same places as the Alport syndrome variants (131 disease-causing).
• Autosomal recessive Alport syndrome is also caused by COL4A3 variants; they fall partly in the same places as the Alport syndrome variants (32 disease-causing).
• Benign familial hematuria is also caused by COL4A3 variants; they fall partly in the same places as the Alport syndrome variants (17 disease-causing).
• Autosomal recessive Alport syndrome is also caused by COL4A4 variants; they fall mostly in different places as the Alport syndrome variants (99 disease-causing).
• Hematuria, benign familial is also caused by COL4A4 variants; they fall partly in the same places as the Alport syndrome variants (51 disease-causing).
• Benign familial hematuria is also caused by COL4A4 variants; they fall partly in the same places as the Alport syndrome variants (17 disease-causing).
• Autosomal dominant Alport syndrome is also caused by COL4A4 variants; they fall mostly in different places as the Alport syndrome variants (6 disease-causing).
• X-linked Alport syndrome is also caused by COL4A5 variants; they fall mostly in different places as the Alport syndrome variants (341 disease-causing).

Diseases related to Alport syndrome

• Autosomal dominant Alport syndrome, also linked to COL4A3, COL4A4 and COL4A5
• Autosomal recessive Alport syndrome, also linked to COL4A3 and COL4A4
• Hematuria, benign familial, also linked to COL4A3 and COL4A4
• Nephrotic syndrome, also linked to COL4A4 and COL4A5
• Benign familial hematuria, also linked to COL4A3 and COL4A4
• Kidney disorder, also linked to COL4A3 and COL4A5
• X-linked Alport syndrome, also linked to COL4A5
• Rare genetic deafness, also linked to COL4A5
• Monogenic hearing loss, also linked to COL4A5
• Steroid-resistant nephrotic syndrome, also linked to COL4A5
• Polycystic kidney disease, also linked to COL4A4
• Isolated macular dystrophy, also linked to COL4A5

Frequently asked questions

Which genes are linked to Alport syndrome?

In CATVariant, Alport syndrome is linked to 3 analyzed proteins: COL4A3 (Collagen alpha-3(IV) chain), COL4A4 (Collagen alpha-4(IV) chain) and COL4A5 (Collagen alpha-5(IV) chain).

How many genetic variants are linked to Alport syndrome?

575 variants: 199 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 315 are of uncertain significance or have conflicting reports.

Which uncertain variants in Alport syndrome look disease-causing?

6 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example COL4A4 G1066R, COL4A3 G1164D, COL4A3 G662E, COL4A3 G985V and COL4A3 G1083R. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Alport syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.99, based on 39 disease-causing and 37 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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