Neonatal severe primary hyperparathyroidism: genes and variants
Neonatal severe primary hyperparathyroidism is linked to 1 analyzed protein (CASR). 11 DNA variants are known to cause it; 45 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 Neonatal severe primary hyperparathyroidism
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.
11 disease-causing and 45 uncertain variants in CASR are linked to Neonatal severe primary hyperparathyroidism.
Where Neonatal severe primary hyperparathyroidism variants cluster
- CASR Ligand-binding 1 (LB1) (positions 22–188): 3 of 11 disease-causing changes, 1.8× more than its size predicts.
Known disease-causing variants in Neonatal severe primary hyperparathyroidism
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| CASR R220W | 220 | Ligand-binding 2 (LB2) | Disease-causing (★★) |
| CASR N64D | 64 | Ligand-binding 1 (LB1) | Disease-causing (★★) |
| CASR E127K | 127 | Ligand-binding 1 (LB1) | Disease-causing (★★) |
| CASR G509R | 509 | Extracellular | Disease-causing (★★) |
| CASR G613E | 613 | Transmembrane | Disease-causing (★★) |
| CASR R680H | 680 | Transmembrane | Disease-causing (★★) |
| CASR V689M | 689 | Transmembrane | Disease-causing (★★) |
| CASR F832S | 832 | Extracellular | Disease-causing (★★) |
| CASR R227L | 227 | Ligand-binding 2 (LB2) | Disease-causing (★★) |
| CASR R69S | 69 | Ligand-binding 1 (LB1) | Disease-causing (★) |
| CASR G670E | 670 | Extracellular | Disease-causing |
Which prediction tools work for Neonatal severe primary hyperparathyroidism
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- PolyPhen-2: 93 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)
- SIFT: 83 out of 100
Same protein, different disease
- Familial hypocalciuric hypercalcemia is also caused by CASR variants; they fall mostly in different places as the Neonatal severe primary hyperparathyroidism variants (81 disease-causing).
- Autosomal dominant hypocalcemia is also caused by CASR variants; they fall mostly in different places as the Neonatal severe primary hyperparathyroidism variants (69 disease-causing).
- Nephrolithiasis/nephrocalcinosis is also caused by CASR variants; they fall partly in the same places as the Neonatal severe primary hyperparathyroidism variants (14 disease-causing).
- Epilepsy, idiopathic generalized, susceptibility to, 13 is also caused by CASR variants; they fall in the same places as the Neonatal severe primary hyperparathyroidism variants (8 disease-causing).
- Familial hyperparathyroidism or Hypocalciuric hypercalcaemia is also caused by CASR variants; they fall mostly in different places as the Neonatal severe primary hyperparathyroidism variants (5 disease-causing).
Diseases related to Neonatal severe primary hyperparathyroidism
- 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
- Idiopathic generalized epilepsy, also linked to CASR
- Nephrolithiasis/nephrocalcinosis, 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 Neonatal severe primary hyperparathyroidism?
In CATVariant, Neonatal severe primary hyperparathyroidism is linked to 1 analyzed protein: CASR (Extracellular calcium-sensing receptor).
How many genetic variants are linked to Neonatal severe primary hyperparathyroidism?
66 variants: 11 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 45 are of uncertain significance or have conflicting reports.
Which uncertain variants in Neonatal severe primary hyperparathyroidism 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 Neonatal severe primary hyperparathyroidism?
Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.83, based on 9 disease-causing and 11 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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