Familial hypocalciuric hypercalcemia 1

Summary

Familial hypocalciuric hypercalcemia 1 (MONDO:0007791) is a disease caused by CASR (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: CASR (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 340

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	5.5	Worldwide	Validated
Point prevalence	6-9 / 10 000	74.1	United States	Validated
Point prevalence	1-9 / 100 000	1.3	United Kingdom	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hypocalciuric hypercalcemia 1
Mondo ID	MONDO:0007791
MeSH	C537145
OMIM	145980
Orphanet	93372
DOID	DOID:0060700
SNOMED CT	704166007
UMLS	C0342637
MedGen	137973
GARD	0002796
MedDRA	10068704
Is cancer (heuristic)	no

Also known as: CASR familial hypocalciuric hypercalcemia · familial benign hypercalcemia 1 · familial benign hypercalcemia type 1 · familial hypocalciuric hypercalcemia caused by mutation in CASR · familial hypocalciuric hypercalcemia type 1 · FBH1 · FHH type 1 · HHC1 · hpocalciuric hypercalcemia, type I · hypercalcemia, familial benign type 1 · hypocalciuric hypercalcemia, familial, type 1 · hypocalciuric hypercalcemia, familial, type I

Data availability: 340 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › mineral metabolism disease › calcium metabolic disease › hypercalcemia disease › familial hypocalciuric hypercalcemia › familial hypocalciuric hypercalcemia 1

Related subtypes (2): familial hypocalciuric hypercalcemia 2, familial hypocalciuric hypercalcemia 3

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

340 retrieved; paginated sample, class counts are floors:

133 uncertain significance, 91 conflicting classifications of pathogenicity, 26 pathogenic, 22 pathogenic/likely pathogenic, 22 likely benign, 22 likely pathogenic, 13 benign, 11 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066880	NM_000388.4(CASR):c.1525G>C (p.Gly509Arg)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075778	NM_000388.4(CASR):c.547_548del (p.Phe183fs)	CASR	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
1475268	NM_000388.4(CASR):c.2495T>C (p.Phe832Ser)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1516739	NM_000388.4(CASR):c.2008G>A (p.Gly670Arg)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
1683780	NM_000388.4(CASR):c.2156G>A (p.Trp719Ter)	CASR	Pathogenic	criteria provided, single submitter
1685601	NM_000388.4(CASR):c.139A>G (p.Lys47Glu)	CASR	Pathogenic	criteria provided, single submitter
1697234	NM_000388.4(CASR):c.501T>A (p.Tyr167Ter)	CASR	Pathogenic	no assertion criteria provided
1698608	NM_000388.4(CASR):c.2065G>A (p.Val689Met)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203424	NM_000388.4(CASR):c.2440TTC[1] (p.Phe815del)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
237763	NM_000388.4(CASR):c.2039G>A (p.Arg680His)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279731	NM_000388.4(CASR):c.164C>T (p.Pro55Leu)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
280657	NM_000388.4(CASR):c.108dup (p.Leu37fs)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
3028915	NM_000388.4(CASR):c.1711G>T (p.Gly571Trp)	CASR	Pathogenic	no assertion criteria provided
35787	NM_000388.4(CASR):c.206G>A (p.Arg69His)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372315	NM_000388.4(CASR):c.73C>T (p.Arg25Ter)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374153	NM_000388.4(CASR):c.2449G>A (p.Val817Ile)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
379931	NM_000388.4(CASR):c.2405A>G (p.Asn802Ser)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
379932	NM_000388.4(CASR):c.2657G>C (p.Arg886Pro)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
410347	NM_000388.4(CASR):c.2038C>T (p.Arg680Cys)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
430465	NM_000388.4(CASR):c.649G>T (p.Asp217Tyr)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
431804	NM_000388.4(CASR):c.658C>T (p.Arg220Trp)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
448997	NM_000388.4(CASR):c.659G>A (p.Arg220Gln)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4755438	NM_000388.4(CASR):c.624G>A (p.Trp208Ter)	CASR	Pathogenic	criteria provided, single submitter
532618	NM_000388.4(CASR):c.679C>T (p.Arg227Ter)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60667	NM_000388.4(CASR):c.662C>T (p.Pro221Leu)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
8312	NM_000388.4(CASR):c.2383C>T (p.Arg795Trp)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8313	NM_000388.4(CASR):c.889G>A (p.Glu297Lys)	CASR	Pathogenic	criteria provided, single submitter
8314	NM_000388.4(CASR):c.554G>A (p.Arg185Gln)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
8315	NM_000388.4(CASR):c.380A>C (p.Glu127Ala)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 4 · 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	familial hypocalciuric hypercalcemia 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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CASR	HGNC:1514	ENSG00000036828	P41180	Extracellular calcium-sensing receptor	gencc,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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	23.9×	0.042

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

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
diaphragm	1
hair follicle	1
islet of Langerhans	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CASR	2,692

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CASR	P41180	31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 evidence-associated genes (1 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 1 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	292.8×	0.024	CASR
GPCR ligand binding	1	64.2×	0.030	CASR
G alpha (q) signalling events	1	57.4×	0.030	CASR
GPCR downstream signalling	1	43.4×	0.030	CASR
Signaling by GPCR	1	40.1×	0.030	CASR
G alpha (i) signalling events	1	39.0×	0.030	CASR
Signal Transduction	1	10.2×	0.098	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 1 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	8426.0×	0.003	CASR
chemosensory behavior	1	3370.4×	0.003	CASR
bile acid secretion	1	3370.4×	0.003	CASR
response to fibroblast growth factor	1	2106.5×	0.003	CASR
fat pad development	1	1685.2×	0.003	CASR
cellular response to peptide	1	1685.2×	0.003	CASR
cellular response to vitamin D	1	1532.0×	0.003	CASR
positive regulation of positive chemotaxis	1	1404.3×	0.003	CASR
detection of calcium ion	1	1123.5×	0.003	CASR
cellular response to hepatocyte growth factor stimulus	1	1123.5×	0.003	CASR
positive regulation of calcium ion import	1	936.2×	0.003	CASR
cellular response to low-density lipoprotein particle stimulus	1	887.0×	0.003	CASR
regulation of calcium ion transport	1	802.5×	0.003	CASR
branching morphogenesis of an epithelial tube	1	732.7×	0.003	CASR
positive regulation of vasoconstriction	1	601.9×	0.003	CASR
positive regulation of NLRP3 inflammasome complex assembly	1	581.1×	0.003	CASR
vasodilation	1	366.4×	0.005	CASR
JNK cascade	1	271.8×	0.006	CASR
cellular response to glucose stimulus	1	267.5×	0.006	CASR
positive regulation of insulin secretion	1	255.3×	0.006	CASR
response to ischemia	1	251.5×	0.006	CASR
chloride transmembrane transport	1	237.3×	0.006	CASR
ossification	1	227.7×	0.006	CASR
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	218.9×	0.006	CASR
intracellular calcium ion homeostasis	1	145.3×	0.009	CASR
anatomical structure morphogenesis	1	139.3×	0.009	CASR
phospholipase C-activating G protein-coupled receptor signaling pathway	1	131.7×	0.009	CASR
cellular response to hypoxia	1	121.2×	0.009	CASR
positive regulation of ERK1 and ERK2 cascade	1	85.1×	0.013	CASR
positive regulation of gene expression	1	38.7×	0.028	CASR

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

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: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

10 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
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

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	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.