X-linked Alport syndrome: genes and variants

Genes linked to X-linked 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.

  341 disease-causing and 178 uncertain variants in COL4A5 are linked to X-linked Alport syndrome.

Known disease-causing variants in X-linked Alport syndrome

Showing 60 of 341.

Uncertain variants in X-linked Alport syndrome that look disease-causing

Which prediction tools work for X-linked 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)
• AlphaMissense: 99 out of 100
• CATVariant: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 99 out of 100
• PolyPhen-2: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 97 out of 100
• MutPred2: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 96 out of 100
• phyloP: 94 out of 100

Same protein, different disease

• Alport syndrome is also caused by COL4A5 variants; they fall in the same places as the X-linked Alport syndrome variants (14 disease-causing).

Diseases related to X-linked Alport syndrome

• Alport syndrome, also linked to COL4A5
• Autosomal dominant Alport syndrome, also linked to COL4A5
• Rare genetic deafness, also linked to COL4A5
• Nephrotic syndrome, also linked to COL4A5
• Monogenic hearing loss, also linked to COL4A5
• Steroid-resistant nephrotic syndrome, also linked to COL4A5
• Isolated macular dystrophy, also linked to COL4A5
• Kidney disorder, also linked to COL4A5
• Chronic kidney disease, also linked to COL4A5

Frequently asked questions

Which genes are linked to X-linked Alport syndrome?

In CATVariant, X-linked Alport syndrome is linked to 1 analyzed protein: COL4A5 (Collagen alpha-5(IV) chain).

How many genetic variants are linked to X-linked Alport syndrome?

635 variants: 341 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 178 are of uncertain significance or have conflicting reports.

Which uncertain variants in X-linked Alport syndrome look disease-causing?

20 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example COL4A5 G893D, COL4A5 G722E, COL4A5 G1170S, COL4A5 G412E and COL4A5 G183D. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for X-linked 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 240 disease-causing and 34 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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