Autosomal recessive Alport syndrome: genes and variants

Genes linked to Autosomal recessive 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.

  99 disease-causing and 293 uncertain variants in COL4A4 are linked to Autosomal recessive 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.

  32 disease-causing and 50 uncertain variants in COL4A3 are linked to Autosomal recessive Alport syndrome.

Weakly linked (only a few uncertain records): CACNA1D.

Known disease-causing variants in Autosomal recessive Alport syndrome

Showing 60 of 131.

Uncertain variants in Autosomal recessive Alport syndrome that look disease-causing

Which prediction tools work for Autosomal recessive Alport syndrome

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

• CATVariant: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 98 out of 100
• MetaLR: 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)
• CADD: 92 out of 100
• SIFT: 90 out of 100

Same protein, different disease

• Alport syndrome is also caused by COL4A4 variants; they fall partly in the same places as the Autosomal recessive Alport syndrome variants (57 disease-causing).
• Benign familial hematuria is also caused by COL4A4 variants; they fall in the same places as the Autosomal recessive Alport syndrome variants (17 disease-causing).
• Autosomal dominant Alport syndrome is also caused by COL4A4 variants; they fall partly in the same places as the Autosomal recessive Alport syndrome variants (6 disease-causing).
• Autosomal dominant Alport syndrome is also caused by COL4A3 variants; they fall mostly in different places as the Autosomal recessive Alport syndrome variants (131 disease-causing).
• Alport syndrome is also caused by COL4A3 variants; they fall mostly in different places as the Autosomal recessive Alport syndrome variants (128 disease-causing).
• Hematuria, benign familial is also caused by COL4A3 variants; they fall mostly in different places as the Autosomal recessive Alport syndrome variants (59 disease-causing).
• Benign familial hematuria is also caused by COL4A3 variants; they fall mostly in different places as the Autosomal recessive Alport syndrome variants (17 disease-causing).

Diseases related to Autosomal recessive Alport syndrome

• Alport syndrome, also linked to COL4A3 and COL4A4
• Autosomal dominant Alport syndrome, also linked to COL4A3 and COL4A4
• Hematuria, benign familial, also linked to COL4A3 and COL4A4
• Benign familial hematuria, also linked to COL4A3 and COL4A4
• Nephrotic syndrome, also linked to COL4A4
• Polycystic kidney disease, also linked to COL4A4
• Kidney disorder, also linked to COL4A3
• Focal segmental glomerulosclerosis, also linked to COL4A4

Frequently asked questions

Which genes are linked to Autosomal recessive Alport syndrome?

In CATVariant, Autosomal recessive Alport syndrome is linked to 2 analyzed proteins: COL4A4 (Collagen alpha-4(IV) chain) and COL4A3 (Collagen alpha-3(IV) chain).

How many genetic variants are linked to Autosomal recessive Alport syndrome?

534 variants: 131 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 344 are of uncertain significance or have conflicting reports.

Which uncertain variants in Autosomal recessive Alport syndrome look disease-causing?

7 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example COL4A4 G1066R, COL4A4 G199R, COL4A4 G1106D, COL4A4 G202D and COL4A4 G1069E. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Autosomal recessive Alport syndrome?

Among tools not trained on clinical labels, phyloP separates this disease's known disease-causing variants from harmless ones best (AUROC 0.98, based on 71 disease-causing and 115 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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