Nephrolithiasis/nephrocalcinosis: genes and variants
Nephrolithiasis/nephrocalcinosis is linked to 2 analyzed proteins (CASR and OCRL). 14 DNA variants are known to cause it; 619 more are uncertain, and 0 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to Nephrolithiasis/nephrocalcinosis
CASR: Extracellular calcium-sensing receptor
It senses extracellular calcium in the parathyroid gland and kidney and adjusts parathyroid-hormone secretion and renal calcium handling accordingly. Loss-of-function variants cause familial hypocalciuric hypercalcemia or neonatal severe hyperparathyroidism, whereas activating variants cause autosomal dominant hypocalcemia.
14 disease-causing and 576 uncertain variants in CASR are linked to Nephrolithiasis/nephrocalcinosis.
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.
0 disease-causing and 43 uncertain variants in OCRL are linked to Nephrolithiasis/nephrocalcinosis.
Where Nephrolithiasis/nephrocalcinosis variants cluster
- CASR Ligand-binding 1 (LB1) (positions 22–188): 6 of 14 disease-causing changes, 2.8× more than its size predicts.
Known disease-causing variants in Nephrolithiasis/nephrocalcinosis
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| CASR F128L | 128 | Ligand-binding 1 (LB1) | Disease-causing (★★) |
| CASR T138M | 138 | Ligand-binding 1 (LB1) | Disease-causing (★★) |
| CASR P55L | 55 | Ligand-binding 1 (LB1) | Disease-causing (★★) |
| CASR R66H | 66 | Ligand-binding 1 (LB1) | Disease-causing (★★) |
| CASR R69H | 69 | Ligand-binding 1 (LB1) | Disease-causing (★★) |
| CASR D217Y | 217 | Ligand-binding 2 (LB2) | Disease-causing (★★) |
| CASR R465Q | 465 | Extracellular | Disease-causing (★★) |
| CASR I555T | 555 | Cysteine-rich (CR) | Disease-causing (★★) |
| CASR E767K | 767 | Extracellular | Disease-causing (★★) |
| CASR F788C | 788 | Transmembrane | Disease-causing (★★) |
| CASR G143R | 143 | Ligand-binding 1 (LB1) | Disease-causing (★★) |
| CASR F612S | 612 | Transmembrane | Disease-causing (★) |
| CASR M1L | 1 | Disease-causing (★) | |
| CASR Y829C | 829 | Extracellular | Disease-causing (★) |
Which prediction tools work for Nephrolithiasis/nephrocalcinosis
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- PolyPhen-2: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- SIFT: 72 out of 100
Same protein, different disease
- Familial hypocalciuric hypercalcemia is also caused by CASR variants; they fall mostly in different places as the Nephrolithiasis/nephrocalcinosis variants (81 disease-causing).
- Autosomal dominant hypocalcemia is also caused by CASR variants; they fall mostly in different places as the Nephrolithiasis/nephrocalcinosis variants (69 disease-causing).
- Neonatal severe primary hyperparathyroidism is also caused by CASR variants; they fall partly in the same places as the Nephrolithiasis/nephrocalcinosis variants (11 disease-causing).
- Epilepsy, idiopathic generalized, susceptibility to, 13 is also caused by CASR variants; they fall partly in the same places as the Nephrolithiasis/nephrocalcinosis variants (8 disease-causing).
- Familial hyperparathyroidism or Hypocalciuric hypercalcaemia is also caused by CASR variants; they fall mostly in different places as the Nephrolithiasis/nephrocalcinosis variants (5 disease-causing).
Diseases related to Nephrolithiasis/nephrocalcinosis
- Hypertrophic cardiomyopathy, also linked to CASR
- Familial hypocalciuric hypercalcemia, also linked to CASR
- Autosomal dominant hypocalcemia, also linked to CASR
- Epilepsy, idiopathic generalized, susceptibility to, 13, also linked to CASR
- Dent disease, also linked to OCRL
- Idiopathic generalized epilepsy, also linked to CASR
- Lowe syndrome, also linked to OCRL
- Neonatal severe primary hyperparathyroidism, also linked to CASR
- Familial hyperparathyroidism or Hypocalciuric hypercalcaemia, also linked to CASR
- Familial hypoparathyroidism, also linked to CASR
- Chronic kidney disease, also linked to CASR
Frequently asked questions
Which genes are linked to Nephrolithiasis/nephrocalcinosis?
In CATVariant, Nephrolithiasis/nephrocalcinosis is linked to 2 analyzed proteins: CASR (Extracellular calcium-sensing receptor) and OCRL (Inositol polyphosphate 5-phosphatase OCRL).
How many genetic variants are linked to Nephrolithiasis/nephrocalcinosis?
652 variants: 14 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 619 are of uncertain significance or have conflicting reports.
Which uncertain variants in Nephrolithiasis/nephrocalcinosis 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 Nephrolithiasis/nephrocalcinosis?
Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.72, based on 12 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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