Atypical hemolytic-uremic syndrome: genes and variants

Genes linked to Atypical hemolytic-uremic syndrome

• CFH: Complement factor H

  It restrains the alternative complement pathway on host surfaces and in plasma, protecting tissues from uncontrolled complement amplification. Pathogenic variants or risk alleles are associated with atypical hemolytic uremic syndrome, C3 glomerulopathy, and age-related macular degeneration.

  12 disease-causing and 25 uncertain variants in CFH are linked to Atypical hemolytic-uremic syndrome.

• C3: Complement C3

  It is cleaved during complement activation to generate C3a and C3b, which amplify inflammation, opsonize targets, and drive formation of downstream complement complexes. Deficiency causes severe susceptibility to bacterial infection, while dysregulated activation contributes to complement-mediated kidney and inflammatory diseases.

  5 disease-causing and 63 uncertain variants in C3 are linked to Atypical hemolytic-uremic syndrome.

• HBB: Hemoglobin subunit beta

  Beta-globin, one of the two major protein chains in adult hemoglobin. Hemoglobin uses these chains to transport oxygen from the lungs to tissues, and HBB variants are associated with sickle-cell disease and beta-thalassemia.

  1 disease-causing and 0 uncertain variants in HBB are linked to Atypical hemolytic-uremic syndrome.

• C5: Complement C5

  Its cleavage produces the potent inflammatory mediator C5a and C5b, which initiates assembly of the membrane-attack complex. Excessive activation contributes to several complement-mediated disorders, making C5 blockade an established therapeutic strategy.

  0 disease-causing and 0 uncertain variants in C5 are linked to Atypical hemolytic-uremic syndrome.

Weakly linked (only a few uncertain records): COL4A4, ADAMTS13, COL4A3, COL4A5 and NPHS1.

Where Atypical hemolytic-uremic syndrome variants cluster

• CFH Sushi 20 (positions 1170–1230): 4 of 12 disease-causing changes, 6.7× more than its size predicts.
• CFH Sushi 19 (positions 1107–1165): 3 of 12 disease-causing changes, 5.2× more than its size predicts.

Known disease-causing variants in Atypical hemolytic-uremic syndrome

Which prediction tools work for Atypical hemolytic-uremic syndrome

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

• PolyPhen-2: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 81 out of 100
• CATVariant: 80 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 68 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Erythrocytosis, familial, 6 is also caused by HBB variants; they fall mostly in different places as the Atypical hemolytic-uremic syndrome variants (31 disease-causing).
• Beta thalassemia is also caused by HBB variants; they fall mostly in different places as the Atypical hemolytic-uremic syndrome variants (21 disease-causing).
• Beta-thalassemia HBB/LCRB is also caused by HBB variants; they fall mostly in different places as the Atypical hemolytic-uremic syndrome variants (18 disease-causing).
• Heinz body anemia is also caused by HBB variants; they fall mostly in different places as the Atypical hemolytic-uremic syndrome variants (12 disease-causing).
• Hemoglobinopathy is also caused by HBB variants; they fall mostly in different places as the Atypical hemolytic-uremic syndrome variants (12 disease-causing).

Diseases related to Atypical hemolytic-uremic syndrome

• Age related macular degeneration 9, also linked to C3 and CFH
• Retinal disorder, also linked to C3 and CFH
• Erythrocytosis, familial, 6, also linked to HBB
• Malaria, also linked to HBB
• Beta thalassemia, also linked to HBB
• Heinz body anemia, also linked to HBB
• Beta-thalassemia HBB/LCRB, also linked to HBB
• Hemoglobinopathy, also linked to HBB
• Dominant beta-thalassemia, also linked to HBB
• Alpha Thalassemia, also linked to HBB
• METHEMOGLOBINEMIA, BETA TYPE, also linked to HBB
• Factor H deficiency, also linked to CFH

Frequently asked questions

Which genes are linked to Atypical hemolytic-uremic syndrome?

In CATVariant, Atypical hemolytic-uremic syndrome is linked to 4 analyzed proteins: CFH (Complement factor H), C3 (Complement C3), HBB (Hemoglobin subunit beta) and C5 (Complement C5).

How many genetic variants are linked to Atypical hemolytic-uremic syndrome?

133 variants: 18 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 89 are of uncertain significance or have conflicting reports.

Which uncertain variants in Atypical hemolytic-uremic syndrome 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 Atypical hemolytic-uremic syndrome?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.81, based on 17 disease-causing and 332 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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