Familial hypocalciuric hypercalcemia

Summary

Familial hypocalciuric hypercalcemia (MONDO:0018458) is a disease with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 2,307
• Phenotypes (HPO): 21
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0003072	Hypercalcemia	Obligate (100%)
HP:0003127	Hypocalciuria	Obligate (100%)
HP:0003513	Reduced ratio of renal calcium clearance to creatinine clearance	Very frequent (80-99%)
HP:0003529	Parathormone-independent increased renal tubular calcium reabsorption	Very frequent (80-99%)
HP:0002749	Osteomalacia	Frequent (30-79%)
HP:0008732	Renal hypophosphatemia	Frequent (30-79%)
HP:0003072	Hypercalcemia	Frequent (30-79%)
HP:0000934	Chondrocalcinosis	Occasional (5-29%)
HP:0002017	Nausea and vomiting	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002574	Episodic abdominal pain	Occasional (5-29%)
HP:0002918	Hypermagnesemia	Occasional (5-29%)
HP:0004398	Peptic ulcer	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)
HP:0012609	Hypomagnesiuria	Occasional (5-29%)
HP:0000121	Nephrocalcinosis	Excluded (0%)
HP:0000787	Nephrolithiasis	Very rare (<1-4%)
HP:0001733	Pancreatitis	Very rare (<1-4%)
HP:0002199	Hypocalcemic seizures	Very rare (<1-4%)
HP:0002960	Autoimmunity	Very rare (<1-4%)
HP:0012032	Lipoma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hypocalciuric hypercalcemia
Mondo ID	MONDO:0018458
OMIM	145980
Orphanet	405
DOID	DOID:0060699
ICD-11	81374726
NCIT	C123262
SNOMED CT	237885008
UMLS	C1809471
MedGen	369200
GARD	0010828
Is cancer (heuristic)	no

Also known as: familial benign hypercalcemia · familial benign hypocalciuric hypercalcemia · FBH · FBHH · FHH

Data availability: 2,307 ClinVar variants · 1 cell line.

Disease family

An umbrella term covering 3 Mondo subtypes.

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

Related subtypes (2): hypercalcemia, infantile, humoral hypercalcemia of malignancy

Subtypes (3): familial hypocalciuric hypercalcemia 1, 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

600 retrieved; paginated sample, class counts are floors:

353 uncertain significance, 185 likely benign, 31 pathogenic, 20 conflicting classifications of pathogenicity, 5 pathogenic/likely pathogenic, 5 likely pathogenic, 1 benign

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: 0 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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	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

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	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: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04872894	Not specified	COMPLETED	Familial Hypocalciuric Hypercalcemia: Clinical Aspects and Evolution