Hypoparathyroidism

Summary

Hypoparathyroidism (MONDO:0001220) is a disease with 4 cohort genes (1 GWAS associations across 4 studies) and 87 clinical trials. Top therapeutic interventions include parathyroid hormone, palopegteriparatide, and calcitriol.

At a glance

• Cohort genes: 4
• GWAS associations: 1
• ClinVar variants: 4
• Clinical trials: 87

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypoparathyroidism
Mondo ID	MONDO:0001220
EFO	EFO:0009451
MeSH	D007011
DOID	DOID:11199
ICD-10-CM	E20
ICD-11	1708733050
NCIT	C78350
SNOMED CT	36976004
UMLS	C0020626
MedGen	6985
GARD	0006733
Is cancer (heuristic)	no

Also known as: hypoparathyroidism, idiopathic (subtype) · parathyroid, underactivity of

Data availability: 4 ClinVar variants · 1 GWAS association (4 studies) · 6 cell lines.

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

Related subtypes (3): hyperparathyroidism, parathyroid hyperplasia, tumor of parathyroid gland

Subtypes (3): secondary hypoparathyroidism due to impaired parathormon secretion, hereditary hypoparathyroidism, autoimmune hypoparathyroidism

Genetics & variants

GWAS landscape

1 GWAS associations across 4 studies. Top hits map to 0 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs149451470	2e-08	CYP2C56P - GRB14	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90481588	Verma A	2024	434	450,572	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90651573	Liu TY	2025	297	224,577	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90473187	UK Biobank Whole-Genome Sequencing Consortium	2025	245	458,195	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90435719	Zhou W	2018	142	405,386	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	1

MAF distribution

Bucket	Variants
common (>=0.05)	0
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs149451470	2	164367136	G>A		intergenic_variant	CYP2C56P - GRB14	2e-08	Tier 4: intronic/intergenic

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

1 likely pathogenic, 1 pathogenic, 1 conflicting classifications of pathogenicity, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
265154	NM_144997.7(FLCN):c.1062+2T>G	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
1708274	NM_022552.5(DNMT3A):c.1585G>A (p.Asp529Asn)	DNMT3A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2918658	NM_000093.5(COL5A1):c.1842T>G (p.Ser614Arg)	COL5A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3731026	NM_001312909.2(FAM111A):c.1463T>C (p.Ile488Thr)	FAM111A	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL5A1	Orphanet:287	Classical Ehlers-Danlos syndrome
FAM111A	Orphanet:2763	Osteocraniostenosis
FAM111A	Orphanet:93325	Autosomal dominant Kenny-Caffey syndrome
FLCN	Orphanet:122	Birt-Hogg-Dubé syndrome
FLCN	Orphanet:2903	Familial spontaneous pneumothorax
FLCN	Orphanet:422526	Hereditary clear cell renal cell carcinoma
DNMT3A	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
DNMT3A	Orphanet:404443	Tatton-Brown-Rahman syndrome
DNMT3A	Orphanet:658595	DNMT3A-related microcephalic dwarfism
DNMT3A	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features

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
COL5A1	HGNC:2209	ENSG00000130635	P20908	Collagen alpha-1(V) chain	clinvar
FAM111A	HGNC:24725	ENSG00000166801	Q96PZ2	Serine protease FAM111A	clinvar
FLCN	HGNC:27310	ENSG00000154803	Q8NFG4	Folliculin	clinvar
DNMT3A	HGNC:2978	ENSG00000119772	Q9Y6K1	DNA (cytosine-5)-methyltransferase 3A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL5A1	Collagen alpha-1(V) chain	Type V collagen is a member of group I collagen (fibrillar forming collagen).
FAM111A	Serine protease FAM111A	Single-stranded DNA-binding serine protease that mediates the proteolytic cleavage of covalent DNA-protein cross-links (DPCs) during DNA synthesis, thereby playing a key role in maintaining genomic integrity.
FLCN	Folliculin	Multi-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis.
DNMT3A	DNA (cytosine-5)-methyltransferase 3A	Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · 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
Complement	1	67.0×	0.045
Protease	1	9.2×	0.157
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL5A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
FAM111A	Protease	yes		Peptidase_S1_PA,
FLCN	Other/Unknown	no		Folliculin, Folliculin_DENN, Folliculin/SMCR8_longin
DNMT3A	Complement	yes	2.1.1.37	PWWP_dom, C5_MeTfrase, C5_DNA_meth_AS

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
periodontal ligament	1
stromal cell of endometrium	1
tendon of biceps brachii	1
granulocyte	1
monocyte	1
mononuclear cell	1
buccal mucosa cell	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
ganglionic eminence	1
sural nerve	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL5A1	248	ubiquitous	marker	stromal cell of endometrium, periodontal ligament, tendon of biceps brachii
FAM111A	267	ubiquitous	marker	monocyte, mononuclear cell, granulocyte
FLCN	261	ubiquitous	marker	buccal mucosa cell, right hemisphere of cerebellum, cerebellar hemisphere
DNMT3A	223	ubiquitous	marker	sural nerve, ganglionic eminence, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNMT3A	4,771
COL5A1	2,600
FLCN	1,317
FAM111A	926

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNMT3A	Q9Y6K1	43
FLCN	Q8NFG4	4
FAM111A	Q96PZ2	2
COL5A1	P20908	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. 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
SUMOylation of DNA methylation proteins	1	223.9×	0.022	DNMT3A
Fibronectin matrix formation	1	190.3×	0.022	COL5A1
Attachment of bacteria to epithelial cells	1	165.5×	0.022	COL5A1
Syndecan interactions	1	141.0×	0.022	COL5A1
MET activates PTK2 signaling	1	126.9×	0.022	COL5A1
Collagen chain trimerization	1	86.5×	0.022	COL5A1
Signaling by PDGF	1	84.6×	0.022	COL5A1
NCAM1 interactions	1	82.8×	0.022	COL5A1
Developmental Lineage of Pancreatic Ductal Cells	1	76.1×	0.022	COL5A1
Assembly of collagen fibrils and other multimeric structures	1	66.8×	0.022	COL5A1
Amino acids regulate mTORC1	1	66.8×	0.022	FLCN
DNA methylation	1	59.5×	0.022	DNMT3A
Collagen degradation	1	58.6×	0.022	COL5A1
Collagen biosynthesis and modifying enzymes	1	56.8×	0.022	COL5A1
Defective pyroptosis	1	52.1×	0.022	DNMT3A
Non-integrin membrane-ECM interactions	1	51.4×	0.022	COL5A1
PRC2 methylates histones and DNA	1	50.8×	0.022	DNMT3A
ECM proteoglycans	1	50.1×	0.022	COL5A1
RMTs methylate histone arginines	1	48.8×	0.022	DNMT3A
Integrin cell surface interactions	1	44.8×	0.023	COL5A1
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	1	39.2×	0.025	DNMT3A

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
integrin biosynthetic process	1	4213.0×	0.008	COL5A1
negative regulation of cell proliferation involved in kidney development	1	4213.0×	0.008	FLCN
negative regulation of endodermal cell differentiation	1	2106.5×	0.008	COL5A1
cell proliferation involved in kidney development	1	1404.3×	0.008	FLCN
positive regulation of cellular response to hypoxia	1	1404.3×	0.008	DNMT3A
tendon development	1	1053.2×	0.008	COL5A1
eye morphogenesis	1	1053.2×	0.008	COL5A1
negative regulation of post-translational protein modification	1	1053.2×	0.008	FLCN
negative regulation of lysosome organization	1	1053.2×	0.008	FLCN
cellular response to bisphenol A	1	842.6×	0.009	DNMT3A
regulation of pro-B cell differentiation	1	842.6×	0.009	FLCN
negative regulation of brown fat cell differentiation	1	702.2×	0.009	FLCN
autosome genomic imprinting	1	601.9×	0.010	DNMT3A
regulatory ncRNA-mediated heterochromatin formation	1	468.1×	0.011	DNMT3A
regulation of Ras protein signal transduction	1	468.1×	0.011	FLCN
protein-DNA covalent cross-linking repair	1	421.3×	0.012	FAM111A
transposable element silencing by piRNA-mediated DNA methylation	1	280.9×	0.012	DNMT3A
collagen biosynthetic process	1	263.3×	0.012	COL5A1
response to vitamin A	1	263.3×	0.012	DNMT3A
wound healing, spreading of epidermal cells	1	263.3×	0.012	COL5A1
negative regulation of gene expression via chromosomal CpG island methylation	1	263.3×	0.012	DNMT3A
negative regulation of glycolytic process	1	263.3×	0.012	FLCN
cellular response to ethanol	1	263.3×	0.012	DNMT3A
hepatocyte apoptotic process	1	263.3×	0.012	DNMT3A
supramolecular fiber organization	1	263.3×	0.012	COL5A1
response to lead ion	1	234.1×	0.012	DNMT3A
regulation of TOR signaling	1	234.1×	0.012	FLCN
oocyte development	1	234.1×	0.012	DNMT3A
TOR signaling	1	191.5×	0.014	FLCN
negative regulation of Rho protein signal transduction	1	191.5×	0.014	FLCN

Therapeutics

Drugs indicated for this disease

4 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Calcitriol	Approved (phase 4)
Ergocalciferol	Approved (phase 4)
Palopegteriparatide	Approved (phase 4)
Parathyroid Hormone	Approved (phase 4)
Teriparatide Acetate	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Calcium, Encaleret, Teriparatide.

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COL5A1	0	0
FAM111A	0	0
FLCN	0	0
DNMT3A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DNMT3A	120	Binding:118, ADMET:1, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DNMT3A	2.1.1.37	DNA (cytosine-5-)-methyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
DNMT3A	120

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

0 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.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	FAM111A, DNMT3A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	COL5A1, FLCN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DNMT3A	120	—
COL5A1	0	—
FAM111A	0	—
FLCN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 87.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	44
PHASE3	14
PHASE2	11
PHASE1/PHASE2	5
PHASE1	5
PHASE4	4
EARLY_PHASE1	3
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00581828	PHASE4	COMPLETED	Does Treatment of Hypovitaminosis D Increase Calcium Absorption?
NCT02910466	PHASE4	COMPLETED	A Study of Extended Use of Recombinant Human Parathyroid Hormone (rhPTH(1-84)) in Hypoparathyroidism
NCT03324880	PHASE4	COMPLETED	A Study to Learn if Recombinant Human Parathyroid Hormone [rhPTH(1-84)] Can Improve Symptoms and Metabolic Control in Adults With Hypoparathyroidism (BALANCE)
NCT03425747	PHASE4	COMPLETED	Efficacy of Calcium Citrate Versus Calcium Carbonate for the Management of Chronic Hypoparathyroidism
NCT05778071	PHASE3	ACTIVE_NOT_RECRUITING	Evaluation of the Safety and Efficacy of Eneboparatide (AZP-3601) in Patients With Chronic Hypoparathyroidism
NCT07081997	PHASE3	RECRUITING	A Phase 3 Randomized Clinical Trial to Investigate the Safety and Efficacy of Palopegteriparatide at Doses Greater Than 30 μg/Day in Adult Participants With Hypoparathyroidism
NCT00395538	PHASE3	TERMINATED	Effects of PTH Replacement on Bone in Hypoparathyroidism
NCT00473265	PHASE2/PHASE3	COMPLETED	Bone Properties in Hypoparathyroidism: Effects of PTH
NCT00732615	PHASE3	COMPLETED	Use of NPSP558 in the Treatment of Hypoparathyroidism
NCT00856401	PHASE3	UNKNOWN	ADD-ON Study to Existing Hypoparathyroidism Studies
NCT01199614	PHASE3	COMPLETED	HEXT (Hypo EXTended): Effect of PTH on Skeleton in Hypoparathyroidism
NCT01268098	PHASE3	COMPLETED	Study of Safety and Efficacy of a rhPTH[1-84] of Fixed Doses of 25 and 50 mcg in Adults With Hypoparathyroidism (RELAY)
NCT01297309	PHASE3	COMPLETED	A Open-label Study Investigating the Safety and Tolerability of NPSP558, a Recombinant Human Parathyroid Hormone (rhPTH [1-84]), for the Treatment of Adults With Hypoparathyroidism - A Clinical Extension Study (RACE)
NCT01455181	PHASE3	COMPLETED	A Study to Investigate the Safety and Tolerability of NPSP558, for the Treatment of Adults With Hypoparathyroidism - A Clinical Extension Study in Hungary
NCT03364738	PHASE3	TERMINATED	Safety and Efficacy Study of rhPTH(1-84) in Subjects With Hypoparathyroidism
NCT03878953	PHASE3	WITHDRAWN	A Clinical Study of rhPTH(1-84) Treatment in Japanese Participants With Chronic Hypoparathyroidism
NCT04701203	PHASE3	COMPLETED	A Trial Investigating the Safety, Tolerability and Efficacy of TransCon PTH Administered Daily in Adults With Hypoparathyroidism
NCT04750460	PHASE3	COMPLETED	Injection of Teriparatide to Prevent Hypocalcemia After Parathyroidectomy in Dialysis Patients (TeriCa).
NCT05387070	PHASE3	COMPLETED	PaTHway CHINA TRIAL: A Trial to Investigating the Safety, Tolerability and Efficacy of TransCon PTH in Adults With Hypoparathyroidism
NCT06531941	PHASE2	ACTIVE_NOT_RECRUITING	Extension Study to Evaluate the Long-Term Safety and Tolerability of MBX 2109 in Patients With Hypoparathyroidism
NCT06547151	PHASE2	RECRUITING	Evaluating the Safety and Efficacy of AMOR-1 as a Treatment for Hypocalcemia Associated With Hypoparathyroidism in Adults
NCT06961071	PHASE1/PHASE2	RECRUITING	Parathyroid Allotransplant for Treatment of Hypoparathyroidism
NCT06988670	PHASE2	RECRUITING	A Phase 2 Trial Investigating the Safety, Tolerability and Efficacy of EXT608 in Adults With Hypoparathyroidism
NCT07530705	PHASE1/PHASE2	RECRUITING	Efficacy and Safety of Subcutaneous Injection of XH-02 in the Treatment of Adult Hypoparathyroidism
NCT07540286	PHASE2	RECRUITING	A Cohort Study on the Safety and Efficacy of XH-02 in Treating Hypoparathyroidism
NCT00001304	PHASE2	COMPLETED	Treatment of Hypoparathyroidism With Synthetic Human Parathyroid Hormone 1-34
NCT00730210	PHASE2	COMPLETED	Treatment of Hypoparathyroidism With Subcutaneous PTH (1-84) Injections: Effects on Muscle Function and Quality of Life
NCT00743782	PHASE2	COMPLETED	Comparing Pump With Subcutaneous Injection Delivery of PTH 1-34 in the Management of Chronic Hypoparathyroidism
NCT01815021	PHASE1/PHASE2	COMPLETED	A Study Comparing Amorphous Calcium Carbonate (ACC) Versus Crystalline Calcium CCS) in Hypoparathyroidism Patients
NCT02152228	PHASE2	COMPLETED	A Pilot Study to Assess the Safety and Efficacy of Oral PTH (1-34) in the Treatment of Hypoparathyroidism
NCT03516773	PHASE2	COMPLETED	Oral PTH(1-34) PK and PD Study in Patients With Hypoparathyroidism
NCT04009291	PHASE2	COMPLETED	A Trial Investigating the Safety, Tolerability and Efficacy of TransCon PTH in Adults With Hypoparathyroidism
NCT05186883	PHASE1/PHASE2	UNKNOWN	Treatment of Postoperative Hypoparathyroidism Using Cultured Allogenic Parathyroid Cells
NCT05239221	PHASE1/PHASE2	COMPLETED	AZP-3601 SAD and MAD Study in Healthy Subjects and Patients With Hypoparathyroidism
NCT06465108	PHASE2	COMPLETED	Safety, Pharmacokinetics and Efficacy of MBX 2109 in Patients With Hypoparathyroidism
NCT00566488	PHASE1	COMPLETED	Parathyroid and Thymus Transplantation in DiGeorge #931
NCT02781844	PHASE1	COMPLETED	Study to Assess the Blood Concentrations and Actions of Recombinant Human Parathyroid Hormone (rhPTH [1-84]) When Given Once and Twice Daily to Participants With Hypoparathyroidism
NCT03150108	PHASE1	COMPLETED	Study of rhPTH(1-84) in Japanese Healthy Subjects Compared With Matched Caucasian Healthy Adult Subjects
NCT04209179	PHASE1	TERMINATED	A Clinical Study Investigating the Safety, Tolerability, PK and PD of PCO371 in Patients With Hypoparathyroidism
NCT05965167	PHASE1	COMPLETED	Assess Safety and Compare PK of New Oral hPTH(1-34) Tablet Formulations vs. EBP05 Tablets and Subcutaneous Forteo

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PARATHYROID HORMONE	4	13
PALOPEGTERIPARATIDE	4	5
CALCITRIOL	4	1
CALCIUM	4	1
CALCIUM CARBONATE	4	1
CALCIUM GLUCONATE	4	1
CHOLECALCIFEROL	4	1
ERGOCALCIFEROL	4	1
SODIUM CITRATE	4	1
TERIPARATIDE	4	1
CALCIUM CITRATE	3	1
GLUCAGON-LIKE PEPTIDE II	3	1
ENEBOPARATIDE	2	2
PCO-371	1	1
CHEMBL5072826	0	1