Dent disease: genes and variants

Genes linked to Dent disease

• CLCN5: H(+)/Cl(-) exchange transporter 5

  It supports endosomal acidification and receptor recycling in renal proximal-tubule cells, enabling efficient reabsorption of filtered proteins and solutes. Loss-of-function variants cause Dent disease type 1, with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, and kidney-stone risk.

  15 disease-causing and 42 uncertain variants in CLCN5 are linked to Dent disease.

• OCRL: Inositol polyphosphate 5-phosphatase OCRL

  It dephosphorylates specific phosphoinositides on endosomal and Golgi membranes and thereby regulates membrane trafficking, actin dynamics, and primary-cilium function. Loss-of-function variants cause Lowe syndrome and Dent disease type 2.

  10 disease-causing and 35 uncertain variants in OCRL are linked to Dent disease.

Where Dent disease variants cluster

• OCRL 5-PPase (positions 235–538): 8 of 10 disease-causing changes, 2.4× more than its size predicts.

Known disease-causing variants in Dent disease

Which prediction tools work for Dent disease

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

• PolyPhen-2: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 86 out of 100

Same protein, different disease

• X-linked recessive nephrolithiasis with renal failure is also caused by CLCN5 variants; they fall partly in the same places as the Dent disease variants (3 disease-causing).
• Lowe syndrome is also caused by OCRL variants; they fall partly in the same places as the Dent disease variants (17 disease-causing).

Diseases related to Dent disease

• Lowe syndrome, also linked to OCRL
• Nephrolithiasis/nephrocalcinosis, also linked to OCRL
• Hypophosphatemic rickets, also linked to CLCN5
• Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis, also linked to CLCN5
• X-linked recessive nephrolithiasis with renal failure, also linked to CLCN5

Frequently asked questions

Which genes are linked to Dent disease?

In CATVariant, Dent disease is linked to 2 analyzed proteins: CLCN5 (H(+)/Cl(-) exchange transporter 5) and OCRL (Inositol polyphosphate 5-phosphatase OCRL).

How many genetic variants are linked to Dent disease?

147 variants: 25 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 77 are of uncertain significance or have conflicting reports.

Which uncertain variants in Dent disease 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 Dent disease?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.86, based on 19 disease-causing and 46 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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