Hypoparathyroidism, familial isolated 1

Summary

Hypoparathyroidism, familial isolated 1 (MONDO:0007796) is a disease caused by PTH (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PTH (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypoparathyroidism, familial isolated 1
Mondo ID	MONDO:0007796
OMIM	146200
DOID	DOID:0061150
SNOMED CT	237657009
UMLS	C5241444
MedGen	1713884
GARD	0024578
Is cancer (heuristic)	no

Also known as: FIH · FIH1 · hypoparathyroidism familial isolated · hypoparathyroidism, familial isolated · hypoparathyroidism, familial isolated 1

Data availability: 11 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › parathyroid gland disorder › hypoparathyroidism › hereditary hypoparathyroidism › familial hypoparathyroidism › hypoparathyroidism, familial isolated 1

Related subtypes (2): autosomal dominant hypocalcemia, hypoparathyroidism, familial isolated, 2

Subtypes (2): familial isolated hypoparathyroidism due to agenesis of parathyroid gland, familial isolated hypoparathyroidism due to impaired PTH secretion

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

11 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 3 pathogenic, 2 benign, 1 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13756	NM_000315.4(PTH):c.52T>C (p.Cys18Arg)	PTH	Pathogenic	no assertion criteria provided
13757	NM_000315.4(PTH):c.86+1G>C	PTH	Pathogenic	no assertion criteria provided
13758	NM_000315.4(PTH):c.67T>C (p.Ser23Pro)	PTH	Pathogenic	no assertion criteria provided
4537488	NM_000315.4(PTH):c.1_2insGCAT (p.Met1fs)	PTH	Likely pathogenic	criteria provided, single submitter
3722898	NM_000315.4(PTH):c.168dup (p.Lys57Ter)	PTH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2435280	NM_000315.4(PTH):c.86+4_86+7del	PTH	Uncertain significance	criteria provided, single submitter
2627520	NM_000315.4(PTH):c.98T>A (p.Val33Glu)	PTH	Uncertain significance	criteria provided, single submitter
3892213	NM_000315.4(PTH):c.167G>A (p.Arg56His)	PTH	Uncertain significance	criteria provided, single submitter
4278134	NM_000315.4(PTH):c.128G>A (p.Gly43Glu)	PTH	Uncertain significance	criteria provided, single submitter
255816	NM_000315.4(PTH):c.-5-10G>A	PTH	Benign	criteria provided, multiple submitters, no conflicts
255817	NM_000315.4(PTH):c.247C>A (p.Arg83=)	PTH	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
PTH	Strong	Autosomal dominant	hypoparathyroidism, familial isolated 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PTH	Orphanet:189466	Familial isolated hypoparathyroidism due to impaired PTH secretion

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
PTH	HGNC:9606	ENSG00000152266	P01270	Parathyroid hormone	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PTH	Parathyroid hormone	Parathyroid hormone elevates calcium level by dissolving the salts in bone and preventing their renal excretion.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PTH	Other/Unknown	no		PTH/PTH-rel, PTH

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
endometrium epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTH	1,967

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTH	P01270	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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 B/2 (Secretin family receptors)	1	190.3×	0.011	PTH
G alpha (s) signalling events	1	73.2×	0.014	PTH

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
macromolecule biosynthetic process	1	16852.0×	0.001	PTH
adenylate cyclase-activating G protein-coupled cAMP receptor signaling pathway	1	8426.0×	0.001	PTH
negative regulation of apoptotic process in bone marrow cell	1	5617.3×	0.001	PTH
cAMP metabolic process	1	4213.0×	0.001	PTH
response to parathyroid hormone	1	4213.0×	0.001	PTH
positive regulation of cell proliferation in bone marrow	1	4213.0×	0.001	PTH
positive regulation of osteoclast proliferation	1	4213.0×	0.001	PTH
negative regulation of bone mineralization involved in bone maturation	1	4213.0×	0.001	PTH
hormone-mediated apoptotic signaling pathway	1	3370.4×	0.001	PTH
positive regulation of inositol phosphate biosynthetic process	1	2407.4×	0.002	PTH
response to fibroblast growth factor	1	2106.5×	0.002	PTH
magnesium ion homeostasis	1	1872.4×	0.002	PTH
positive regulation of signal transduction	1	1296.3×	0.002	PTH
phosphate ion homeostasis	1	1053.2×	0.002	PTH
positive regulation of glycogen biosynthetic process	1	991.3×	0.002	PTH
response to lead ion	1	936.2×	0.002	PTH
response to vitamin D	1	802.5×	0.003	PTH
response to cadmium ion	1	732.7×	0.003	PTH
negative regulation of chondrocyte differentiation	1	674.1×	0.003	PTH
bone resorption	1	581.1×	0.003	PTH
positive regulation of D-glucose import across plasma membrane	1	455.5×	0.004	PTH
homeostasis of number of cells within a tissue	1	443.5×	0.004	PTH
positive regulation of bone mineralization	1	391.9×	0.004	PTH
bone mineralization	1	271.8×	0.006	PTH
Rho protein signal transduction	1	247.8×	0.006	PTH
response to ethanol	1	146.5×	0.009	PTH
intracellular calcium ion homeostasis	1	145.3×	0.009	PTH
skeletal system development	1	125.8×	0.011	PTH
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	113.1×	0.011	PTH
regulation of gene expression	1	83.4×	0.015	PTH

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PTH	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PTH

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)
PTH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.