Autosomal dominant hypocalcemia 1
diseaseOn this page
Also known as autosomal dominant hypocalcemia caused by mutation in CASRautosomal dominant hypocalcemia type 1CASR autosomal dominant hypocalcemiaHYPOC1hypocalcemia, autosomal dominanthypocalcemia, autosomal dominant 1hypocalcemia, autosomal dominant type 1hypocalcemia, autosomal dominant, with Bartter syndrome
Summary
Autosomal dominant hypocalcemia 1 (MONDO:0011013) is a disease caused by CASR (GenCC Definitive), with 2 cohort genes and 3 clinical trials. Top therapeutic interventions include encaleret.
At a glance
- Causal gene: CASR (GenCC Definitive)
- Cohort genes: 2
- ClinVar variants: 2,356
- Clinical trials: 3
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | autosomal dominant hypocalcemia 1 |
| Mondo ID | MONDO:0011013 |
| OMIM | 601198 |
| DOID | DOID:0090107 |
| UMLS | C3715128 |
| MedGen | 811594 |
| GARD | 0024767 |
| Is cancer (heuristic) | no |
Also known as: autosomal dominant hypocalcemia caused by mutation in CASR · autosomal dominant hypocalcemia type 1 · CASR autosomal dominant hypocalcemia · HYPOC1 · hypocalcemia, autosomal dominant · hypocalcemia, autosomal dominant 1 · hypocalcemia, autosomal dominant type 1 · hypocalcemia, autosomal dominant, with Bartter syndrome
Data availability: 2,356 ClinVar variants · 2 GenCC gene-disease records.
Disease family
Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant hypocalcemia › autosomal dominant hypocalcemia 1
Related subtypes (1): autosomal dominant hypocalcemia 2
Genetics & variants
GWAS landscape
No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.
Variant details and genetic-evidence tiers
ClinVar germline variants
600 retrieved; paginated sample, class counts are floors:
354 uncertain significance, 186 likely benign, 31 pathogenic, 20 conflicting classifications of pathogenicity, 5 pathogenic/likely pathogenic, 2 benign, 2 likely pathogenic
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 1066835 | NM_000388.4(CASR):c.2415del (p.Lys805fs) | CASR | Pathogenic | criteria provided, single submitter |
| 1066880 | NM_000388.4(CASR):c.1525G>C (p.Gly509Arg) | CASR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1068041 | NM_000388.4(CASR):c.2254del (p.Arg752fs) | CASR | Pathogenic | criteria provided, single submitter |
| 1068215 | NM_000388.4(CASR):c.1376A>G (p.Gln459Arg) | CASR | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1068229 | NM_000388.4(CASR):c.2297_2298dup (p.Glu767fs) | CASR | Pathogenic | criteria provided, single submitter |
| 1070118 | NM_000388.4(CASR):c.1081C>T (p.Gln361Ter) | CASR | Pathogenic | criteria provided, single submitter |
| 1071373 | NC_000003.11:g.(?121973037)(122004038_?)del | CASR | Pathogenic | criteria provided, single submitter |
| 1071398 | NM_000388.4(CASR):c.1783del (p.His595fs) | CASR | Pathogenic | criteria provided, single submitter |
| 1071747 | NM_000388.4(CASR):c.1056G>A (p.Trp352Ter) | CASR | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1074500 | NM_000388.4(CASR):c.924_925dup (p.Gln309fs) | CASR | Pathogenic | criteria provided, single submitter |
| 1074918 | NM_000388.4(CASR):c.1054del (p.Trp352fs) | CASR | Pathogenic | criteria provided, single submitter |
| 1074921 | NM_000388.4(CASR):c.1773_1774del (p.Ser591_Asn592insTer) | CASR | Pathogenic | criteria provided, single submitter |
| 1075778 | NM_000388.4(CASR):c.547_548del (p.Phe183fs) | CASR | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1076659 | NM_000388.4(CASR):c.1868del (p.Gly623fs) | CASR | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1177515 | NM_000388.4(CASR):c.209G>A (p.Trp70Ter) | CASR | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1321376 | NM_000388.4(CASR):c.666del (p.Ile223fs) | CASR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1321411 | NM_000388.4(CASR):c.1A>G (p.Met1Val) | CASR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1361655 | NM_000388.4(CASR):c.186-2A>G | CASR | Pathogenic | criteria provided, single submitter |
| 1373420 | NM_000388.4(CASR):c.1759dup (p.Asp587fs) | CASR | Pathogenic | criteria provided, single submitter |
| 1376400 | NM_000388.4(CASR):c.1557_1560del (p.Glu519fs) | CASR | Pathogenic | criteria provided, single submitter |
| 1377560 | NM_000388.4(CASR):c.2030del (p.Cys677fs) | CASR | Pathogenic | criteria provided, single submitter |
| 1378885 | NM_000388.4(CASR):c.528del (p.Asn176fs) | CASR | Pathogenic | criteria provided, single submitter |
| 1397805 | NM_000388.4(CASR):c.2008G>C (p.Gly670Arg) | CASR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1408979 | NM_000388.4(CASR):c.2533_2545del (p.Ser845fs) | CASR | Pathogenic | criteria provided, single submitter |
| 1425273 | NM_000388.4(CASR):c.1802del (p.Lys601fs) | CASR | Pathogenic | criteria provided, single submitter |
| 1432045 | NM_000388.4(CASR):c.961_962del (p.Ala321fs) | CASR | Pathogenic | criteria provided, single submitter |
| 1442327 | NM_000388.4(CASR):c.2148dup (p.Lys717fs) | CASR | Pathogenic | criteria provided, single submitter |
| 1449397 | NM_000388.4(CASR):c.1852del (p.Leu618fs) | CASR | Pathogenic | criteria provided, single submitter |
| 1451604 | NM_000388.4(CASR):c.349C>T (p.Gln117Ter) | CASR | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1453597 | NM_000388.4(CASR):c.1542T>G (p.Tyr514Ter) | CASR | Pathogenic | criteria provided, single submitter |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 11 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0
GenCC gene–disease validity (cohort genes)
the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.
| Gene | Classification | Inheritance | Disease | Records |
|---|---|---|---|---|
| CASR | Definitive | Autosomal dominant | autosomal dominant hypocalcemia 1 | 11 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| CASR | Orphanet:417 | Neonatal severe primary hyperparathyroidism |
| CASR | Orphanet:428 | Autosomal dominant hypocalcemia |
| CASR | Orphanet:676 | Autosomal dominant hereditary chronic pancreatitis |
| CASR | Orphanet:93372 | Familial hypocalciuric hypercalcemia type 1 |
| CSTA | Orphanet:263534 | Acral peeling skin syndrome |
| CSTA | Orphanet:289586 | Exfoliative ichthyosis |
Cohort genes → proteins
2 cohort genes, 2 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 2 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| CASR | HGNC:1514 | ENSG00000036828 | P41180 | Extracellular calcium-sensing receptor | gencc,clinvar |
| CSTA | HGNC:2481 | ENSG00000121552 | P01040 | Cystatin-A | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| CASR | Extracellular calcium-sensing receptor | G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis. |
| CSTA | Cystatin-A | This is an intracellular thiol proteinase inhibitor. |
Protein-family classification
Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5
Family distribution
Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.
| Family | Genes | Fold | FDR |
|---|---|---|---|
| GPCR | 1 | 12.0× | 0.164 |
| Other/Unknown | 1 | 0.9× | 0.805 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| CASR | GPCR | yes | GPCR_3_Ca_sens_rcpt-rel, GPCR_3, ANF_lig-bd_rcpt | |
| CSTA | Other/Unknown | no | Cystatin_dom, Prot_inh_stefin, Prot_inh_cystat_CS |
Expression context
Cohort genes with no expression data: 0.
2 cohort genes are a single-cell marker in ≥1 SCXA experiment.
Breadth distribution (Bgee present_calls)
| Bucket | Genes |
|---|---|
| narrow (1-5 tissues) | 0 |
| moderate (6-20) | 0 |
| broad (>20) | 2 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| diaphragm | 1 |
| hair follicle | 1 |
| islet of Langerhans | 1 |
| gingiva | 1 |
| oral cavity | 1 |
| pharyngeal mucosa | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| CASR | 63 | tissue_specific | marker | islet of Langerhans, diaphragm, hair follicle |
| CSTA | 248 | ubiquitous | marker | pharyngeal mucosa, oral cavity, gingiva |
Protein interactions among cohort
Intra-cohort edges: 0.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| CASR | 2,692 |
| CSTA | 2,102 |
Structural data
PDB: 2 · AlphaFold-only: 0 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| CASR | P41180 | 31 |
| CSTA | P01040 | 14 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).
Pathways by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Class C/3 (Metabotropic glutamate/pheromone receptors) | 1 | 146.4× | 0.055 | CASR |
| Formation of the cornified envelope | 1 | 43.9× | 0.058 | CSTA |
| GPCR ligand binding | 1 | 32.1× | 0.058 | CASR |
| G alpha (q) signalling events | 1 | 28.7× | 0.058 | CASR |
| GPCR downstream signalling | 1 | 21.7× | 0.058 | CASR |
| Signaling by GPCR | 1 | 20.0× | 0.058 | CASR |
| G alpha (i) signalling events | 1 | 19.5× | 0.058 | CASR |
| Signal Transduction | 1 | 5.1× | 0.187 | CASR |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| regulation of presynaptic membrane potential | 1 | 4213.0× | 0.006 | CASR |
| chemosensory behavior | 1 | 1685.2× | 0.006 | CASR |
| bile acid secretion | 1 | 1685.2× | 0.006 | CASR |
| response to fibroblast growth factor | 1 | 1053.2× | 0.006 | CASR |
| fat pad development | 1 | 842.6× | 0.006 | CASR |
| cellular response to peptide | 1 | 842.6× | 0.006 | CASR |
| cellular response to vitamin D | 1 | 766.0× | 0.006 | CASR |
| peptide cross-linking | 1 | 702.2× | 0.006 | CSTA |
| positive regulation of positive chemotaxis | 1 | 702.2× | 0.006 | CASR |
| detection of calcium ion | 1 | 561.7× | 0.006 | CASR |
| cellular response to hepatocyte growth factor stimulus | 1 | 561.7× | 0.006 | CASR |
| positive regulation of calcium ion import | 1 | 468.1× | 0.006 | CASR |
| cellular response to low-density lipoprotein particle stimulus | 1 | 443.5× | 0.006 | CASR |
| regulation of calcium ion transport | 1 | 401.2× | 0.006 | CASR |
| branching morphogenesis of an epithelial tube | 1 | 366.4× | 0.007 | CASR |
| negative regulation of proteolysis | 1 | 337.0× | 0.007 | CSTA |
| positive regulation of vasoconstriction | 1 | 300.9× | 0.007 | CASR |
| positive regulation of NLRP3 inflammasome complex assembly | 1 | 290.6× | 0.007 | CASR |
| vasodilation | 1 | 183.2× | 0.010 | CASR |
| JNK cascade | 1 | 135.9× | 0.012 | CASR |
| cellular response to glucose stimulus | 1 | 133.8× | 0.012 | CASR |
| positive regulation of insulin secretion | 1 | 127.7× | 0.012 | CASR |
| response to ischemia | 1 | 125.8× | 0.012 | CASR |
| keratinocyte differentiation | 1 | 123.9× | 0.012 | CSTA |
| chloride transmembrane transport | 1 | 118.7× | 0.012 | CASR |
| ossification | 1 | 113.9× | 0.012 | CASR |
| adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway | 1 | 109.4× | 0.012 | CASR |
| intracellular calcium ion homeostasis | 1 | 72.6× | 0.018 | CASR |
| anatomical structure morphogenesis | 1 | 69.6× | 0.018 | CASR |
| phospholipase C-activating G protein-coupled receptor signaling pathway | 1 | 65.8× | 0.018 | CASR |
Therapeutics
Drug target analysis
Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1
Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).
Genes with an approved drug
The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.
| Symbol | Example approved molecule |
|---|---|
| CASR | CINACALCET HYDROCHLORIDE |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| CASR | 10 | 4 |
| CSTA | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| CINACALCET HYDROCHLORIDE | 4 | CASR |
| CINACALCET | 4 | CASR |
| ENCALERET | 3 | CASR |
| EVOCALCET | 3 | CASR |
| SB-423562 | 2 | CASR |
| RONACALERET | 2 | CASR |
| TECALCET HYDROCHLORIDE | 2 | CASR |
| FENDILINE | 2 | CASR |
| TECALCET | 2 | CASR |
| ATF-936 | 1 | CASR |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 0.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| CASR | 45 | Functional:32, Binding:13 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.
No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).
Chemical tractability of cohort targets
9 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.
| Compound | Max phase | Cohort target (bioactivity) |
|---|---|---|
| CINACALCET HYDROCHLORIDE | 4 | CASR |
| CINACALCET | 4 | CASR |
| EVOCALCET | 3 | CASR |
| SB-423562 | 2 | CASR |
| RONACALERET | 2 | CASR |
| TECALCET HYDROCHLORIDE | 2 | CASR |
| FENDILINE | 2 | CASR |
| TECALCET | 2 | CASR |
| ATF-936 | 1 | CASR |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 1 | CASR |
| B | Phased (≥1) drug, not yet approved | 0 | |
| C | Druggable family + PDB, no drug | 0 | |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 1 | CSTA |
Undrugged target profiles
1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| CSTA | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 3.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| PHASE2 | 2 |
| PHASE2/PHASE3 | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT07080385 | PHASE2/PHASE3 | RECRUITING | Pharmacokinetics, Efficacy, and Safety of Encaleret in Pediatric Participants With Autosomal Dominant Hypocalcemia Type 1 (ADH1) |
| NCT00743782 | PHASE2 | COMPLETED | Comparing Pump With Subcutaneous Injection Delivery of PTH 1-34 in the Management of Chronic Hypoparathyroidism |
| NCT04581629 | PHASE2 | COMPLETED | Safety, Tolerability, and Efficacy of Encaleret in Participants With Autosomal Dominant Hypocalcemia (ADH) Type 1 |
Drugs tested across these trials (top 30)
| Molecule | Max phase | Trials referencing |
|---|---|---|
| ENCALERET | 3 | 2 |