Hyperparathyroidism 1

Summary

Hyperparathyroidism 1 (MONDO:0007767) is a disease caused by CDC73 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: CDC73 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 222

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperparathyroidism 1
Mondo ID	MONDO:0007767
MeSH	C564166
OMIM	145000
UMLS	C1840402
MedGen	333554
GARD	0018253
Is cancer (heuristic)	no

Also known as: HRPT1 · hyperparathyroidism 1 · hyperparathyroidism type 1 · hyperparathyroidism, familial primary

Data availability: 222 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › familial isolated hyperparathyroidism › hyperparathyroidism 1

Related subtypes (2): hyperparathyroidism 3, hyperparathyroidism 4

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

222 retrieved; paginated sample, class counts are floors:

135 uncertain significance, 33 conflicting classifications of pathogenicity, 19 benign/likely benign, 12 likely benign, 10 pathogenic, 7 likely pathogenic, 4 benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
560081	Single allele	B3GALT2	Pathogenic	criteria provided, single submitter
1074700	NM_024529.5(CDC73):c.415C>T (p.Arg139Ter)	CDC73	Pathogenic	criteria provided, multiple submitters, no conflicts
1194275	NM_024529.5(CDC73):c.802C>T (p.Arg268Ter)	CDC73	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457825	NM_024529.5(CDC73):c.626_629del (p.Lys209fs)	CDC73	Pathogenic	criteria provided, multiple submitters, no conflicts
241496	NM_024529.5(CDC73):c.687_688dup (p.Val230fs)	CDC73	Pathogenic	criteria provided, multiple submitters, no conflicts
2585772	NM_024529.5(CDC73):c.685A>T (p.Arg229Ter)	CDC73	Pathogenic	criteria provided, multiple submitters, no conflicts
3241015	NM_024529.5(CDC73):c.520_523del (p.Ser174fs)	CDC73	Pathogenic	criteria provided, multiple submitters, no conflicts
3270	NM_024529.5(CDC73):c.679_680insAG (p.Arg227fs)	CDC73	Pathogenic	no assertion criteria provided
3276	NM_024529.5(CDC73):c.131+1G>A	CDC73	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
658835	NM_024529.5(CDC73):c.664C>T (p.Arg222Ter)	CDC73	Pathogenic	criteria provided, multiple submitters, no conflicts
846304	NM_024529.5(CDC73):c.271C>T (p.Arg91Ter)	CDC73	Pathogenic	criteria provided, multiple submitters, no conflicts
16707	NM_001370259.2(MEN1):c.1350+1G>A	MEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
2771148	NM_024529.5(CDC73):c.513-1G>A	CDC73	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3272	NM_024529.5(CDC73):c.191T>C (p.Leu64Pro)	CDC73	Likely pathogenic	criteria provided, single submitter
3382714	NM_024529.5(CDC73):c.127dup (p.Trp43fs)	CDC73	Likely pathogenic	criteria provided, single submitter
3574849	NM_024529.5(CDC73):c.512+1del	CDC73	Likely pathogenic	criteria provided, single submitter
3574863	NM_024529.5(CDC73):c.549del (p.Ala184fs)	CDC73	Likely pathogenic	criteria provided, single submitter
375573	NM_024529.5(CDC73):c.132-2A>G	CDC73	Likely pathogenic	criteria provided, single submitter
4531369	NM_024529.5(CDC73):c.908-2A>G	CDC73	Likely pathogenic	criteria provided, single submitter
1054916	NM_024529.5(CDC73):c.116A>G (p.Asn39Ser)	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
133841	NM_024529.5(CDC73):c.1149C>A (p.Asp383Glu)	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
133842	NM_024529.5(CDC73):c.412C>A (p.Pro138Thr)	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1794894	NM_024529.5(CDC73):c.1009G>A (p.Ala337Thr)	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2070736	NM_024529.5(CDC73):c.973-18A>G	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
21680	NM_024529.5(CDC73):c.-11G>A	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
241494	NM_024529.5(CDC73):c.1333G>A (p.Val445Ile)	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2680424	NM_024529.5(CDC73):c.424-12G>A	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
294410	NM_024529.5(CDC73):c.156A>G (p.Arg52=)	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
294411	NM_024529.5(CDC73):c.201G>A (p.Val67=)	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
294413	NM_024529.5(CDC73):c.834C>T (p.Pro278=)	CDC73	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 10 · 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
CDC73	Definitive	Autosomal dominant	hyperparathyroidism 2 with jaw tumors	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CDC73	Orphanet:143	Parathyroid carcinoma
CDC73	Orphanet:99879	Familial isolated hyperparathyroidism
CDC73	Orphanet:99880	Hyperparathyroidism-jaw tumor syndrome
MEN1	Orphanet:2965	Prolactinoma
MEN1	Orphanet:314786	Silent pituitary adenoma
MEN1	Orphanet:314790	Null pituitary adenoma
MEN1	Orphanet:652	Multiple endocrine neoplasia type 1
MEN1	Orphanet:97279	Insulinoma
MEN1	Orphanet:99725	Pituitary gigantism
MEN1	Orphanet:99879	Familial isolated hyperparathyroidism

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CDC73	HGNC:16783	ENSG00000134371	Q6P1J9	Parafibromin	gencc,clinvar
MEN1	HGNC:7010	ENSG00000133895	O00255	Menin	clinvar
B3GALT2	HGNC:917	ENSG00000162630	O43825	Beta-1,3-galactosyltransferase 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDC73	Parafibromin	Tumor suppressor probably involved in transcriptional and post-transcriptional control pathways.
MEN1	Menin	Essential component of a MLL/SET1 histone methyltransferase (HMT) complex, a complex that specifically methylates ‘Lys-4’ of histone H3 (H3K4).
B3GALT2	Beta-1,3-galactosyltransferase 2	Beta-1,3-galactosyltransferase that transfers galactose from UDP-galactose to substrates with a terminal beta-N-acetylglucosamine (beta-GlcNAc) residue.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CDC73	Other/Unknown	no		Cdc73/Parafibromin, CDC73_C, Cdc73_N
MEN1	Other/Unknown	no		Menin
B3GALT2	Enzyme (other)	yes	2.4.1.62	Glyco_trans_31, B3GT2_N

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
colonic epithelium	1
sural nerve	1
granulocyte	1
lower esophagus mucosa	1
right hemisphere of cerebellum	1
cortical plate	1
endothelial cell	1
heart right ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDC73	271	ubiquitous	marker	calcaneal tendon, sural nerve, colonic epithelium
MEN1	271	ubiquitous	marker	granulocyte, lower esophagus mucosa, right hemisphere of cerebellum
B3GALT2	200	broad	yes	cortical plate, heart right ventricle, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MEN1	5,226
CDC73	4,592
B3GALT2	632

Intra-cohort edges

A	B	Sources
B3GALT2	CDC73	string_interaction
CDC73	MEN1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MEN1	O00255	69
CDC73	Q6P1J9	20

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
B3GALT2	O43825	78.89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 37. Enrichment computed across 3 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
Formation of the beta-catenin:TCF transactivating complex	2	80.1×	0.003	CDC73, MEN1
TCF dependent signaling in response to WNT	2	78.5×	0.003	CDC73, MEN1
Signaling by WNT	2	74.6×	0.003	CDC73, MEN1
Blood group systems biosynthesis	1	380.7×	0.024	B3GALT2
Protein ubiquitination	1	271.9×	0.027	CDC73
Lewis blood group biosynthesis	1	223.9×	0.028	B3GALT2
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	122.8×	0.028	MEN1
RHO GTPases activate IQGAPs	1	115.3×	0.028	MEN1
Dengue virus activates/modulates innate and adaptive immune responses	1	112.0×	0.028	CDC73
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	102.9×	0.028	MEN1
RNA Polymerase II Transcription	2	15.0×	0.028	CDC73, MEN1
Post-translational protein modification	2	12.8×	0.028	CDC73, MEN1
Gene expression (Transcription)	2	11.9×	0.028	CDC73, MEN1
Formation of WDR5-containing histone-modifying complexes	1	88.5×	0.030	MEN1
Deactivation of the beta-catenin transactivating complex	1	77.7×	0.030	MEN1
Signaling by TGF-beta Receptor Complex	1	66.8×	0.030	MEN1
Formation of RNA Pol II elongation complex	1	64.5×	0.030	CDC73
RNA Polymerase II Transcription Elongation	1	64.5×	0.030	CDC73
E3 ubiquitin ligases ubiquitinate target proteins	1	64.5×	0.030	CDC73
Signaling by Hedgehog	1	61.4×	0.030	CDC73
Hedgehog ‘on’ state	1	52.9×	0.031	CDC73
Epigenetic regulation by WDR5-containing histone modifying complexes	1	51.4×	0.031	MEN1
Metabolism of proteins	2	8.2×	0.031	CDC73, MEN1
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	48.8×	0.031	MEN1
RNA Polymerase II Pre-transcription Events	1	45.9×	0.032	CDC73
Metabolism of carbohydrates and carbohydrate derivatives	1	40.1×	0.035	B3GALT2
Signaling by TGFB family members	1	38.5×	0.035	MEN1
CHD1 and CHD2 subfamily	1	36.2×	0.035	CDC73
Signal Transduction	2	6.8×	0.035	CDC73, MEN1
Post-translational protein phosphorylation	1	33.4×	0.037	MEN1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glucosylceramide metabolic process	1	1872.4×	0.011	B3GALT2
positive regulation of mRNA 3’-end processing	1	1123.5×	0.011	CDC73
endodermal cell fate commitment	1	936.2×	0.011	CDC73
negative regulation of cyclin-dependent protein serine/threonine kinase activity	1	702.2×	0.011	MEN1
T-helper 2 cell differentiation	1	624.1×	0.011	MEN1
negative regulation of cell population proliferation	2	28.1×	0.011	CDC73, MEN1
positive regulation of cell cycle G1/S phase transition	1	374.5×	0.014	CDC73
osteoblast development	1	330.4×	0.014	MEN1
negative regulation of myeloid cell differentiation	1	312.1×	0.014	CDC73
obsolete negative regulation of DNA-binding transcription factor activity	1	244.2×	0.014	MEN1
oligosaccharide biosynthetic process	1	216.1×	0.014	B3GALT2
negative regulation of protein phosphorylation	1	193.7×	0.014	MEN1
response to gamma radiation	1	193.7×	0.014	MEN1
mRNA 3’-end processing	1	187.2×	0.014	CDC73
negative regulation of JNK cascade	1	187.2×	0.014	MEN1
positive regulation of transforming growth factor beta receptor signaling pathway	1	175.5×	0.014	MEN1
negative regulation of fibroblast proliferation	1	165.2×	0.014	CDC73
transcription elongation by RNA polymerase II	1	147.8×	0.014	CDC73
stem cell population maintenance	1	140.4×	0.014	CDC73
positive regulation of Wnt signaling pathway	1	127.7×	0.014	CDC73
transcription initiation-coupled chromatin remodeling	1	127.7×	0.014	MEN1
response to UV	1	122.1×	0.014	MEN1
negative regulation of G1/S transition of mitotic cell cycle	1	119.5×	0.014	CDC73
glycoprotein biosynthetic process	1	112.3×	0.014	B3GALT2
positive regulation of transcription elongation by RNA polymerase II	1	100.3×	0.014	CDC73
negative regulation of osteoblast differentiation	1	98.5×	0.014	MEN1
protein destabilization	1	96.8×	0.014	CDC73
negative regulation of cell cycle	1	96.8×	0.014	MEN1
negative regulation of epithelial cell proliferation	1	96.8×	0.014	CDC73
negative regulation of transcription by RNA polymerase II	2	11.8×	0.014	CDC73, MEN1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
MEN1	LOPERAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MEN1	475	4
CDC73	1	2
B3GALT2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LOPERAMIDE	4	MEN1
CANDESARTAN CILEXETIL	4	MEN1
EVANS BLUE FREE ACID	4	MEN1
DIENESTROL	4	MEN1
BEXAROTENE	4	MEN1
IFOSFAMIDE	4	MEN1
PROGESTERONE	4	MEN1
CLOTRIMAZOLE	4	MEN1
AMINOCAPROIC ACID	4	MEN1
LATANOPROST	4	MEN1
FLUORESCEIN	4	MEN1
OXCARBAZEPINE	4	MEN1
SALMETEROL XINAFOATE	4	MEN1
AMIODARONE HYDROCHLORIDE	4	MEN1
TRICLABENDAZOLE	4	MEN1
TRYPAN BLUE FREE ACID	4	MEN1
MIGALASTAT	4	MEN1
DROPERIDOL	4	MEN1
ARIPIPRAZOLE	4	MEN1
AMOXAPINE	4	MEN1
RALOXIFENE HYDROCHLORIDE	4	MEN1
IDARUBICIN	4	MEN1
ACETAMINOPHEN	4	MEN1
OXYBUTYNIN CHLORIDE	4	MEN1
DECAMETHONIUM BROMIDE	4	MEN1
DESLORATADINE	4	MEN1
DITHIAZANINE	4	MEN1
TRIMETREXATE	4	MEN1
NICARDIPINE HYDROCHLORIDE	4	MEN1
PROTRIPTYLINE HYDROCHLORIDE	4	MEN1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MEN1	93	Binding:86, Functional:7
CDC73	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
B3GALT2	2.4.1.62	ganglioside galactosyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
LOPERAMIDE	4	MEN1
CANDESARTAN CILEXETIL	4	MEN1
EVANS BLUE FREE ACID	4	MEN1
DIENESTROL	4	MEN1
BEXAROTENE	4	MEN1
IFOSFAMIDE	4	MEN1
PROGESTERONE	4	MEN1
CLOTRIMAZOLE	4	MEN1
AMINOCAPROIC ACID	4	MEN1
LATANOPROST	4	MEN1
FLUORESCEIN	4	MEN1
OXCARBAZEPINE	4	MEN1
SALMETEROL XINAFOATE	4	MEN1
AMIODARONE HYDROCHLORIDE	4	MEN1
TRICLABENDAZOLE	4	MEN1
TRYPAN BLUE FREE ACID	4	MEN1
MIGALASTAT	4	MEN1
DROPERIDOL	4	MEN1
ARIPIPRAZOLE	4	MEN1
AMOXAPINE	4	MEN1
RALOXIFENE HYDROCHLORIDE	4	MEN1
IDARUBICIN	4	MEN1
ACETAMINOPHEN	4	MEN1
OXYBUTYNIN CHLORIDE	4	MEN1
DECAMETHONIUM BROMIDE	4	MEN1
DESLORATADINE	4	MEN1
DITHIAZANINE	4	MEN1
TRIMETREXATE	4	MEN1
NICARDIPINE HYDROCHLORIDE	4	MEN1
PROTRIPTYLINE HYDROCHLORIDE	4	MEN1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MEN1
B	Phased (≥1) drug, not yet approved	1	CDC73
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	B3GALT2
E	Difficult family or no structure, no drug	0

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)
B3GALT2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.