Hemochromatosis: genes and variants

Genes linked to Hemochromatosis

• SLC40A1: Ferroportin

  It exports iron from enterocytes, macrophages, and hepatocytes into the circulation and is directly inhibited by hepcidin. Pathogenic variants cause ferroportin disease or hepcidin-resistant iron overload, depending on whether they impair export or hepcidin regulation.

  37 disease-causing and 69 uncertain variants in SLC40A1 are linked to Hemochromatosis.

• HFE: Hereditary hemochromatosis protein

  It helps the liver sense circulating iron availability and regulate hepcidin, thereby controlling intestinal iron absorption and systemic iron distribution. The C282Y variant is the major genetic cause of HFE-related hereditary hemochromatosis and progressive iron overload.

  5 disease-causing and 19 uncertain variants in HFE are linked to Hemochromatosis.

Where Hemochromatosis variants cluster

• SLC40A1 Transmembrane (positions 165–195): 7 of 37 disease-causing changes, 3.5× more than its size predicts.
• SLC40A1 Transmembrane (positions 127–162): 7 of 37 disease-causing changes, 3.0× more than its size predicts.
• SLC40A1 Transmembrane (positions 58–84): 5 of 37 disease-causing changes, 2.9× more than its size predicts.
• SLC40A1 Transmembrane (positions 203–229): 5 of 37 disease-causing changes, 2.9× more than its size predicts.
• SLC40A1 Transmembrane (positions 307–333): 4 of 37 disease-causing changes, 2.3× more than its size predicts.

Known disease-causing variants in Hemochromatosis

Which prediction tools work for Hemochromatosis

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

• PolyPhen-2: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 86 out of 100
• SIFT: 85 out of 100
• phyloP: 85 out of 100

Diseases related to Hemochromatosis

• Alzheimer disease, also linked to HFE
• Microvascular complications of diabetes, susceptibility to, 3, also linked to HFE
• Hereditary hemochromatosis, also linked to HFE
• Familial porphyria cutanea tarda, also linked to HFE

Frequently asked questions

Which genes are linked to Hemochromatosis?

In CATVariant, Hemochromatosis is linked to 2 analyzed proteins: SLC40A1 (Ferroportin) and HFE (Hereditary hemochromatosis protein).

How many genetic variants are linked to Hemochromatosis?

163 variants: 42 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 88 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hemochromatosis 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 Hemochromatosis?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.85, based on 13 disease-causing and 9 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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