Familial hypoparathyroidism

Summary

Familial hypoparathyroidism (MONDO:0016390) is a disease with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 4
• ClinVar variants: 133
• Phenotypes (HPO): 19

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0000829	Hypoparathyroidism	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0002901	Hypocalcemia	Very frequent (80-99%)
HP:0003198	Myopathy	Very frequent (80-99%)
HP:0100530	Abnormality of calcium-phosphate metabolism	Very frequent (80-99%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000682	Abnormality of dental enamel	Frequent (30-79%)
HP:0000684	Delayed eruption of teeth	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0002514	Cerebral calcification	Frequent (30-79%)
HP:0002905	Hyperphosphatemia	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0003472	Hypocalcemic tetany	Frequent (30-79%)
HP:0011675	Arrhythmia	Frequent (30-79%)
HP:0007352	Cerebellar calcifications	Occasional (5-29%)
HP:0000112	Nephropathy	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0025425	Laryngospasm	Occasional (5-29%)
HP:0031627	Globus pallidus calcification	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hypoparathyroidism
Mondo ID	MONDO:0016390
MeSH	C537156
OMIM	146200
Orphanet	2238
DOID	DOID:0111387
ICD-11	1907423603
SNOMED CT	725036000
UMLS	C1832648
MedGen	322005
GARD	0002910
NORD	1128
Is cancer (heuristic)	no

Also known as: Familial Isolated Hypoparathyroidism · familial isolated hypoparathyroidism · hypoparathyroidism familial isolated · hypoparathyroidism, familial · hypoparathyroidism, familial isolated

Data availability: 133 ClinVar variants.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › parathyroid gland disorder › hypoparathyroidism › hereditary hypoparathyroidism › familial hypoparathyroidism

Related subtypes (2): autoimmune polyendocrine syndrome type 1, pseudohypoparathyroidism

Subtypes (3): hypoparathyroidism, familial isolated 1, autosomal dominant hypocalcemia, hypoparathyroidism, familial isolated, 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

133 retrieved; paginated sample, class counts are floors:

54 uncertain significance, 32 conflicting classifications of pathogenicity, 23 benign, 14 benign/likely benign, 5 pathogenic, 4 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
60667	NM_000388.4(CASR):c.662C>T (p.Pro221Leu)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
8323	NM_000388.4(CASR):c.452C>T (p.Thr151Met)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
2691426	NM_004752.4(GCM2):c.22G>T (p.Glu8Ter)	GCM2	Pathogenic	criteria provided, single submitter
3769019	NC_000006.11:g.(10875167_10876123)(10882275?)del	GCM2	Pathogenic	criteria provided, single submitter
433164	NM_004752.4(GCM2):c.408C>A (p.Tyr136Ter)	GCM2	Pathogenic	criteria provided, multiple submitters, no conflicts
35785	NM_000388.4(CASR):c.1934C>A (p.Ala645Asp)	CASR	Likely pathogenic	criteria provided, single submitter
1917623	NM_004752.4(GCM2):c.90+2T>G	GCM2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4540628	NM_002067.5(GNA11):c.535G>A (p.Val179Met)	GNA11	Likely pathogenic	criteria provided, single submitter
13759	NM_000315.4(PTH):c.247C>T (p.Arg83Ter)	PTH	Likely pathogenic	criteria provided, single submitter
196262	NM_000388.4(CASR):c.748G>A (p.Glu250Lys)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
237755	NM_000388.4(CASR):c.1188A>G (p.Thr396=)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
237758	NM_000388.4(CASR):c.1631G>A (p.Arg544Gln)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
237759	NM_000388.4(CASR):c.1752G>A (p.Lys584=)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
237762	NM_000388.4(CASR):c.2064C>T (p.Phe688=)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
257606	NM_000388.4(CASR):c.1733-9A>G	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285281	NM_000388.4(CASR):c.60C>T (p.Tyr20=)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
342792	NM_000388.4(CASR):c.-154T>A	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
342794	NM_000388.4(CASR):c.-111C>A	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
342795	NM_000388.4(CASR):c.6A>C (p.Ala2=)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
342797	NM_000388.4(CASR):c.930C>T (p.Tyr310=)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
342798	NM_000388.4(CASR):c.1008G>C (p.Lys336Asn)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
342799	NM_000388.4(CASR):c.1665T>C (p.Ile555=)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
342800	NM_000388.4(CASR):c.1923C>T (p.Pro641=)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
342802	NM_000388.4(CASR):c.2915C>T (p.Thr972Met)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
342803	NM_000388.4(CASR):c.2955C>T (p.Asn985=)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
342804	NM_000388.4(CASR):c.3054C>T (p.Cys1018=)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
342805	NM_000388.4(CASR):c.3168G>T (p.Val1056=)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
410351	NM_000388.4(CASR):c.2147G>A (p.Arg716His)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
431803	NM_000388.4(CASR):c.-10C>T	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
532595	NM_000388.4(CASR):c.2255G>A (p.Arg752His)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 15 · 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
GCM2	Orphanet:2239	Familial isolated hypoparathyroidism due to agenesis of parathyroid gland
GCM2	Orphanet:99879	Familial isolated hyperparathyroidism
GNA11	Orphanet:101049	Familial hypocalciuric hypercalcemia type 2
GNA11	Orphanet:1556	Cutis marmorata telangiectatica congenita
GNA11	Orphanet:39044	Uveal melanoma
GNA11	Orphanet:428	Autosomal dominant hypocalcemia
GNA11	Orphanet:675359	Anastomosing haemangioma
GNA11	Orphanet:714737	Diffuse capillary malformation with overgrowth
GNA11	Orphanet:79483	Phakomatosis cesioflammea
GNA11	Orphanet:79484	Phakomatosis cesiomarmorata
PTH	Orphanet:189466	Familial isolated hypoparathyroidism due to impaired PTH secretion

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CASR	HGNC:1514	ENSG00000036828	P41180	Extracellular calcium-sensing receptor	clinvar
GCM2	HGNC:4198	ENSG00000124827	O75603	Chorion-specific transcription factor GCMb	clinvar
GNA11	HGNC:4379	ENSG00000088256	P29992	Guanine nucleotide-binding protein subunit alpha-11	clinvar
PTH	HGNC:9606	ENSG00000152266	P01270	Parathyroid hormone	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.
GCM2	Chorion-specific transcription factor GCMb	Transcription factor that binds specific sequences on gene promoters and activate their transcription.
GNA11	Guanine nucleotide-binding protein subunit alpha-11	Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades.
PTH	Parathyroid hormone	Parathyroid hormone elevates calcium level by dissolving the salts in bone and preventing their renal excretion.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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	6.0×	0.314
Other/Unknown	3	1.3×	0.404

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
GCM2	Other/Unknown	no		Tscrpt_reg_GCM, GCM_dom_sf, GCM
GNA11	Other/Unknown	no		Gprotein_alpha_Q, Gprotein_alpha_su, GproteinA_insert
PTH	Other/Unknown	no		PTH/PTH-rel, PTH

Expression context

Cohort genes with no expression data: 0.

3 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)	1
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	2
male germ line stem cell (sensu Vertebrata) in testis	2
pancreatic ductal cell	2
diaphragm	1
hair follicle	1
islet of Langerhans	1
jejunal mucosa	1
endometrium epithelium	1
pigmented layer of retina	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
GCM2	9	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell, ileal mucosa
GNA11	299	ubiquitous	marker	ileal mucosa, jejunal mucosa, pancreatic ductal cell
PTH	94	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, pigmented layer of retina, endometrium epithelium

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CASR	2,692
PTH	1,967
GNA11	1,873
GCM2	892

Intra-cohort edges

A	B	Sources
CASR	GCM2	string_interaction
CASR	GNA11	string_interaction
CASR	PTH	string_interaction
GCM2	GNA11	string_interaction
GCM2	PTH	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CASR	P41180	31
PTH	P01270	26
GNA11	P29992	13

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GCM2	O75603	58.78

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion	1	475.8×	0.017	GNA11
Acetylcholine regulates insulin secretion	1	380.7×	0.017	GNA11
G alpha (q) signalling events	2	38.3×	0.017	CASR, GNA11
G-protein activation	1	158.6×	0.019	GNA11
Thromboxane signalling through TP receptor	1	158.6×	0.019	GNA11
ADP signalling through P2Y purinoceptor 1	1	152.3×	0.019	GNA11
Thrombin signalling through proteinase activated receptors (PARs)	1	119.0×	0.019	GNA11
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	119.0×	0.019	GNA11
Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding	1	100.2×	0.019	GNA11
Class C/3 (Metabotropic glutamate/pheromone receptors)	1	97.6×	0.019	CASR
PLC beta mediated events	1	88.5×	0.019	GNA11
Class B/2 (Secretin family receptors)	1	63.4×	0.025	PTH
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	53.6×	0.027	GNA11
G alpha (s) signalling events	1	24.4×	0.055	PTH
GPCR ligand binding	1	21.4×	0.058	CASR
GPCR downstream signalling	1	14.5×	0.079	CASR
Signaling by GPCR	1	13.4×	0.079	CASR
G alpha (i) signalling events	1	13.0×	0.079	CASR
Signal Transduction	1	3.4×	0.267	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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to fibroblast growth factor	2	1053.2×	5e-05	CASR, PTH
intracellular calcium ion homeostasis	3	109.0×	5e-05	CASR, GCM2, PTH
positive regulation of insulin secretion	2	127.7×	0.003	CASR, GNA11
macromolecule biosynthetic process	1	4213.0×	0.004	PTH
regulation of melanocyte differentiation	1	4213.0×	0.004	GNA11
regulation of presynaptic membrane potential	1	2106.5×	0.004	CASR
adenylate cyclase-activating G protein-coupled cAMP receptor signaling pathway	1	2106.5×	0.004	PTH
phospholipase C-activating G protein-coupled receptor signaling pathway	2	65.8×	0.004	CASR, GNA11
skeletal system development	2	62.9×	0.004	GNA11, PTH
negative regulation of apoptotic process in bone marrow cell	1	1404.3×	0.005	PTH
cAMP metabolic process	1	1053.2×	0.005	PTH
response to parathyroid hormone	1	1053.2×	0.005	PTH
positive regulation of cell proliferation in bone marrow	1	1053.2×	0.005	PTH
positive regulation of osteoclast proliferation	1	1053.2×	0.005	PTH
negative regulation of bone mineralization involved in bone maturation	1	1053.2×	0.005	PTH
chemosensory behavior	1	842.6×	0.005	CASR
hormone-mediated apoptotic signaling pathway	1	842.6×	0.005	PTH
bile acid secretion	1	842.6×	0.005	CASR
transcription by RNA polymerase II	2	35.3×	0.005	GCM2, PTH
entrainment of circadian clock	1	702.2×	0.006	GNA11
gliogenesis	1	702.2×	0.006	GCM2
parathyroid gland development	1	601.9×	0.006	GCM2
positive regulation of inositol phosphate biosynthetic process	1	601.9×	0.006	PTH
phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway	1	526.6×	0.006	GNA11
developmental pigmentation	1	526.6×	0.006	GNA11
phospholipase C-activating dopamine receptor signaling pathway	1	526.6×	0.006	GNA11
cellular response to pH	1	526.6×	0.006	GNA11
magnesium ion homeostasis	1	468.1×	0.006	PTH
ligand-gated ion channel signaling pathway	1	468.1×	0.006	GNA11
fat pad development	1	421.3×	0.006	CASR

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
GCM2	0	0
GNA11	0	0
PTH	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
GNA11	18	Binding:18

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	3	GCM2, GNA11, PTH

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GCM2	0	CASR
GNA11	18	CASR
PTH	0	CASR

Clinical trials & evidence

Clinical trials

Clinical trials: 0.