Renal tubulopathies: genes and variants

Genes linked to Renal tubulopathies

• SLC12A3: Solute carrier family 12 member 3

  It reabsorbs sodium and chloride in the distal convoluted tubule and is a major determinant of renal salt and magnesium handling. Biallelic loss-of-function variants cause Gitelman syndrome with hypokalemic metabolic alkalosis, hypomagnesemia, and low urinary calcium.

  14 disease-causing and 6 uncertain variants in SLC12A3 are linked to Renal tubulopathies.

• SLC4A1: Band 3 anion transport protein

  In red blood cells it exchanges chloride and bicarbonate to support carbon-dioxide transport, while in renal intercalated cells it is required for acid-base regulation. Pathogenic variants can cause hereditary spherocytosis or distal renal tubular acidosis depending on the affected function.

  1 disease-causing and 1 uncertain variants in SLC4A1 are linked to Renal tubulopathies.

• AVPR2: Vasopressin V2 receptor

  1 disease-causing and 0 uncertain variants in AVPR2 are linked to Renal tubulopathies.

Weakly linked (only a few uncertain records): ATP6V1B1.

Known disease-causing variants in Renal tubulopathies

Which prediction tools work for Renal tubulopathies

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

• CADD: 95 out of 100
• PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 88 out of 100
• SIFT: 82 out of 100

Same protein, different disease

• Familial hypokalemia-hypomagnesemia is also caused by SLC12A3 variants; they fall mostly in different places as the Renal tubulopathies variants (115 disease-causing).
• Hereditary spherocytosis is also caused by SLC4A1 variants; they fall mostly in different places as the Renal tubulopathies variants (13 disease-causing).
• Autosomal dominant distal renal tubular acidosis is also caused by SLC4A1 variants; they fall mostly in different places as the Renal tubulopathies variants (11 disease-causing).
• Cryohydrocytosis is also caused by SLC4A1 variants; they fall mostly in different places as the Renal tubulopathies variants (9 disease-causing).
• Diabetes insipidus, nephrogenic, X-linked is also caused by AVPR2 variants; they fall mostly in different places as the Renal tubulopathies variants (25 disease-causing).
• Nephrogenic diabetes insipidus is also caused by AVPR2 variants; they fall mostly in different places as the Renal tubulopathies variants (7 disease-causing).
• Nephrogenic syndrome of inappropriate antidiuresis is also caused by AVPR2 variants; they fall mostly in different places as the Renal tubulopathies variants (7 disease-causing).

Diseases related to Renal tubulopathies

• Familial hypokalemia-hypomagnesemia, also linked to SLC12A3
• Nephrotic syndrome, also linked to SLC12A3
• Nephrogenic diabetes insipidus, also linked to AVPR2
• Diabetes insipidus, nephrogenic, X-linked, also linked to AVPR2
• Hereditary spherocytosis, also linked to SLC4A1
• Autosomal dominant polycystic kidney disease, also linked to AVPR2
• Autosomal dominant distal renal tubular acidosis, also linked to SLC4A1
• Cryohydrocytosis, also linked to SLC4A1
• Nephrogenic syndrome of inappropriate antidiuresis, also linked to AVPR2
• Myocardial infarction, also linked to SLC12A3
• Bartter syndrome, also linked to SLC12A3
• Southeast Asian ovalocytosis, also linked to SLC4A1

Frequently asked questions

Which genes are linked to Renal tubulopathies?

In CATVariant, Renal tubulopathies is linked to 3 analyzed proteins: SLC12A3 (Solute carrier family 12 member 3), SLC4A1 (Band 3 anion transport protein) and AVPR2 (Vasopressin V2 receptor).

How many genetic variants are linked to Renal tubulopathies?

24 variants: 16 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 8 are of uncertain significance or have conflicting reports.

Which uncertain variants in Renal tubulopathies 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 Renal tubulopathies?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.95, based on 16 disease-causing and 63 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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