pseudohypoparathyroidism type 1B

Summary

pseudohypoparathyroidism type 1B (MONDO:0011301) is a disease caused by variants in GNAS and STX16, with 5 cohort genes.

At a glance

• Prevalence: Unknown (Europe) [Orphanet-validated]
• Causal genes: GNAS (GenCC Definitive), STX16 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 297
• Phenotypes (HPO): 39

Clinical features

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0000852	Pseudohypoparathyroidism	Obligate (100%)
HP:0002901	Hypocalcemia	Very frequent (80-99%)
HP:0002905	Hyperphosphatemia	Very frequent (80-99%)
HP:0003165	Elevated circulating parathyroid hormone level	Very frequent (80-99%)
HP:0003456	Low urinary cyclic AMP response to PTH administration	Very frequent (80-99%)
HP:0000293	Full cheeks	Frequent (30-79%)
HP:0000311	Round face	Frequent (30-79%)
HP:0000470	Short neck	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000684	Delayed eruption of teeth	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0006297	Enamel hypoplasia	Frequent (30-79%)
HP:0000509	Conjunctivitis	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001657	Prolonged QT interval	Occasional (5-29%)
HP:0002094	Dyspnea	Occasional (5-29%)
HP:0003034	Diaphyseal sclerosis	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0003401	Paresthesia	Occasional (5-29%)
HP:0003472	Hypocalcemic tetany	Occasional (5-29%)
HP:0003739	Myoclonic spasms	Occasional (5-29%)
HP:0003909	Cortical subperiosteal resorption of humeral metaphyses	Occasional (5-29%)
HP:0005700	Increased bone density with cystic changes	Occasional (5-29%)
HP:0011001	Increased bone mineral density	Occasional (5-29%)
HP:0011458	Abdominal symptom	Occasional (5-29%)
HP:0012049	Laryngeal dystonia	Occasional (5-29%)
HP:0100660	Dyskinesia	Occasional (5-29%)
HP:0100749	Chest pain	Occasional (5-29%)
HP:0003761	Calcinosis	Excluded (0%)
HP:0010766	Ectopic calcification	Excluded (0%)
HP:0030057	Autoimmune antibody positivity	Excluded (0%)
HP:0000824	Decreased response to growth hormone stimulation test	Very rare (<1-4%)
HP:0002199	Hypocalcemic seizures	Very rare (<1-4%)
HP:0008227	Pituitary resistance to thyroid hormone	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pseudohypoparathyroidism type 1B
Mondo ID	MONDO:0011301
MeSH	C548075
OMIM	603233
Orphanet	94089
DOID	DOID:0080222
ICD-11	440485628
UMLS	C1864100
MedGen	350343
GARD	0010680
Is cancer (heuristic)	no

Also known as: PHP1B · pseudohypoparathyroidism Ib · pseudohypoparathyroidism, type IB

Data availability: 297 ClinVar variants · 9 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn metal metabolism disorder › pseudohypoparathyroidism › pseudohypoparathyroidism type 1B

Related subtypes (4): pseudohypoparathyroidism type 1A, pseudohypoparathyroidism type 2, pseudohypoparathyroidism type 1C, pseudopseudohypoparathyroidism

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

297 retrieved; paginated sample, class counts are floors:

171 uncertain significance, 47 benign, 25 likely benign, 17 pathogenic, 15 benign/likely benign, 12 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065886	NM_000516.7(GNAS):c.682C>T (p.Arg228Cys)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1212	GNAS, 4.7-KB DEL	GNAS	Pathogenic	no assertion criteria provided
1217738	NM_000516.7(GNAS):c.91C>T (p.Gln31Ter)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1455167	NM_000516.7(GNAS):c.1024C>T (p.Arg342Ter)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
15927	NM_000516.7(GNAS):c.1A>G (p.Met1Val)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
15933	NM_000516.7(GNAS):c.601C>T (p.Arg201Cys)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15934	NM_000516.7(GNAS):c.602G>A (p.Arg201His)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15938	NM_000516.7(GNAS):c.565_568del (p.Asp189fs)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15960	NG_016194.2:g.[6012_6117gom;19440_19569lom]	GNAS	Pathogenic	no assertion criteria provided
209158	NM_000516.7(GNAS):c.34C>T (p.Gln12Ter)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
3373471	NM_000516.7(GNAS):c.445_446del (p.His149fs)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3587590	NM_000516.7(GNAS):c.970+1G>C	GNAS	Pathogenic	criteria provided, single submitter
374113	NM_000516.7(GNAS):c.85C>T (p.Gln29Ter)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
3767107	NM_000516.7(GNAS):c.433-2A>C	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4531299	NM_000516.7(GNAS):c.585+1G>C	GNAS	Pathogenic	criteria provided, single submitter
816910	NM_000516.7(GNAS):c.691C>T (p.Arg231Cys)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
871093	NM_000516.7(GNAS):c.348dup (p.Val117fs)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
873534	NM_000516.7(GNAS):c.139+1G>C	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
930857	NM_000516.7(GNAS):c.296del (p.Leu99fs)	GNAS	Pathogenic	criteria provided, single submitter
4277543	NM_001001433.3(STX16):c.556+1G>A	STX16	Pathogenic	criteria provided, single submitter
6149	NM_001001433.3(STX16):c.145-2060_556+343del	STX16	Pathogenic	no assertion criteria provided
625617	GRCh37/hg19 20q13.32(chr20:57244540-57246216)	STX16	Pathogenic	criteria provided, single submitter
978043	NM_001001433.3(STX16):c.393+557_792+364del	STX16	Pathogenic	criteria provided, single submitter
1334571	NM_000516.7(GNAS):c.124dup (p.Arg42fs)	GNAS	Likely pathogenic	criteria provided, single submitter
3065653	NM_080425.4(GNAS):c.648del (p.Gly215_Tyr216insTer)	GNAS	Likely pathogenic	criteria provided, single submitter
4057287	NM_000516.7(GNAS):c.1173C>G (p.Tyr391Ter)	GNAS	Likely pathogenic	criteria provided, single submitter
623189	NM_000516.7(GNAS):c.1143CAT[1] (p.Ile383del)	GNAS	Likely pathogenic	criteria provided, single submitter
1205909	NM_080425.4(GNAS):c.154G>A (p.Glu52Lys)	GNAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134492	NM_080425.4(GNAS):c.988A>G (p.Ile330Val)	GNAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1803837	NM_080425.4(GNAS):c.707A>G (p.Asp236Gly)	GNAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 27 · Orphanet: 12 · 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
GNAS	Definitive	Autosomal dominant	pseudohypoparathyroidism type 1A	21
STX16	Strong	Autosomal dominant	pseudohypoparathyroidism type 1B	4
GNAS-AS1	Limited	Unknown	pseudohypoparathyroidism type 1B	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STX16	Orphanet:94089	Pseudohypoparathyroidism type 1B
GNAS	Orphanet:189427	Cushing syndrome due to bilateral macronodular adrenocortical disease
GNAS	Orphanet:2762	Progressive osseous heteroplasia
GNAS	Orphanet:562	McCune-Albright syndrome
GNAS	Orphanet:57782	Mazabraud syndrome
GNAS	Orphanet:79443	Pseudohypoparathyroidism type 1A
GNAS	Orphanet:79444	Pseudohypoparathyroidism type 1C
GNAS	Orphanet:79445	Pseudopseudohypoparathyroidism
GNAS	Orphanet:93276	Polyostotic fibrous dysplasia
GNAS	Orphanet:93277	Monostotic fibrous dysplasia
GNAS	Orphanet:94089	Pseudohypoparathyroidism type 1B
GHSR	Orphanet:314811	Short stature due to GHSR deficiency

Cohort genes → proteins

5 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STX16	HGNC:11431	ENSG00000124222	O14662	Syntaxin-16	gencc,clinvar
GNAS-AS1	HGNC:24872	ENSG00000235590		GNAS antisense RNA 1	gencc,clinvar
GNAS	HGNC:4392	ENSG00000087460	O95467	Neuroendocrine secretory protein 55	gencc,clinvar
STX16-NPEPL1	HGNC:41993	ENSG00000254995		STX16-NPEPL1 readthrough (NMD candidate)	clinvar
GHSR	HGNC:4267	ENSG00000121853	Q92847	Growth hormone secretagogue receptor type 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STX16	Syntaxin-16	SNARE involved in vesicular transport from the late endosomes to the trans-Golgi network.
GHSR	Growth hormone secretagogue receptor type 1	G-protein-coupled receptor specific to ghrelin, an appetite-regulating peptide hormone commonly found in stomach.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.2

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	4.8×	0.269
Other/Unknown	4	1.4×	0.269

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STX16	Other/Unknown	no		T_SNARE_dom, Syntaxin/epimorphin_CS, SNARE
GNAS-AS1	Other/Unknown	no
GNAS	Other/Unknown	no		NESP55, Gprotein_alpha_S, Gprotein_alpha_su
STX16-NPEPL1	Other/Unknown	no
GHSR	GPCR	yes		GPCR_Rhodpsn, GHS-R/MTLR, GPCR_Rhodpsn_7TM

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)	0
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	2
corpus callosum	1
right uterine tube	1
sural nerve	1
cortical plate	1
tibia	1
Brodmann (1909) area 46	1
postcentral gyrus	1
type B pancreatic cell	1
granulocyte	1
mucosa of stomach	1
right hemisphere of cerebellum	1
adenohypophysis	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STX16	300	broad	marker	right uterine tube, sural nerve, corpus callosum
GNAS-AS1	148	broad	yes	islet of Langerhans, cortical plate, tibia
GNAS	312	ubiquitous	marker	type B pancreatic cell, postcentral gyrus, Brodmann (1909) area 46
STX16-NPEPL1	133	ubiquitous	yes	mucosa of stomach, right hemisphere of cerebellum, granulocyte
GHSR	30		marker	pituitary gland, islet of Langerhans, adenohypophysis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STX16	1,793
GHSR	1,083
GNAS	410
GNAS-AS1	0
STX16-NPEPL1	0

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAS	O95467	490
GHSR	Q92847	10
STX16	O14662	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 5 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
PKA activation in glucagon signalling	1	223.9×	0.025	GNAS
Prostacyclin signalling through prostacyclin receptor	1	200.3×	0.025	GNAS
Glucagon signaling in metabolic regulation	1	115.3×	0.025	GNAS
Glucagon-type ligand receptors	1	115.3×	0.025	GNAS
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	88.5×	0.025	GNAS
Vasopressin regulates renal water homeostasis via Aquaporins	1	88.5×	0.025	GNAS
Intra-Golgi traffic	1	86.5×	0.025	STX16
ADORA2B mediated anti-inflammatory cytokines production	1	84.6×	0.025	GNAS
GPER1 signaling	1	82.8×	0.025	GNAS
G alpha (z) signalling events	1	77.7×	0.025	GNAS
Retrograde transport at the Trans-Golgi-Network	1	73.2×	0.025	STX16
Hedgehog ‘off’ state	1	59.5×	0.028	GNAS
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	53.6×	0.029	GNAS
Intra-Golgi and retrograde Golgi-to-ER traffic	1	34.9×	0.041	STX16
Peptide ligand-binding receptors	1	24.7×	0.051	GHSR
G alpha (s) signalling events	1	24.4×	0.051	GNAS
G alpha (q) signalling events	1	19.1×	0.060	GHSR
G alpha (i) signalling events	1	13.0×	0.083	GNAS
Membrane Trafficking	1	12.4×	0.083	STX16
Vesicle-mediated transport	1	11.6×	0.084	STX16

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
regulation of hindgut contraction	1	5617.3×	0.004	GHSR
ghrelin secretion	1	2808.7×	0.004	GHSR
regulation of transmission of nerve impulse	1	2808.7×	0.004	GHSR
negative regulation of locomotion involved in locomotory behavior	1	2808.7×	0.004	GHSR
positive regulation of small intestinal transit	1	2808.7×	0.004	GHSR
regulation of gastric motility	1	2808.7×	0.004	GHSR
positive regulation of appetite	1	1872.4×	0.004	GHSR
adenylate cyclase-activating G protein-coupled bile acid receptor signaling pathway	1	1872.4×	0.004	GNAS
regulation of growth hormone secretion	1	1872.4×	0.004	GHSR
positive regulation of small intestine smooth muscle contraction	1	1872.4×	0.004	GHSR
response to follicle-stimulating hormone	1	1404.3×	0.005	GHSR
response to parathyroid hormone	1	1404.3×	0.005	GNAS
adenylate cyclase-activating serotonin receptor signaling pathway	1	1123.5×	0.005	GNAS
positive regulation of fatty acid metabolic process	1	1123.5×	0.005	GHSR
hair follicle placode formation	1	1123.5×	0.005	GNAS
negative regulation of norepinephrine secretion	1	936.2×	0.005	GHSR
regulation of skeletal muscle contraction	1	936.2×	0.005	GNAS
growth hormone secretion	1	936.2×	0.005	GHSR
negative regulation of macrophage apoptotic process	1	936.2×	0.005	GHSR
cellular response to catecholamine stimulus	1	802.5×	0.005	GNAS
positive regulation of eating behavior	1	802.5×	0.005	GHSR
adult feeding behavior	1	561.7×	0.006	GHSR
response to L-glutamate	1	561.7×	0.006	GHSR
adenylate cyclase-activating dopamine receptor signaling pathway	1	510.7×	0.006	GNAS
negative regulation of appetite	1	510.7×	0.006	GHSR
intracellular transport	1	510.7×	0.006	GNAS
cellular response to thyroid hormone stimulus	1	510.7×	0.006	GHSR
response to prostaglandin E	1	468.1×	0.006	GNAS
cellular response to insulin-like growth factor stimulus	1	432.1×	0.006	GHSR
positive regulation of insulin-like growth factor receptor signaling pathway	1	401.2×	0.006	GHSR

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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
GHSR	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GHSR	113	4
STX16	0	0
GNAS-AS1	0	0
GNAS	0	0
STX16-NPEPL1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	GHSR
DIBUCAINE	4	GHSR
RIMONABANT	4	GHSR
ARIPIPRAZOLE	4	GHSR
IDARUBICIN	4	GHSR
DICYCLOMINE	4	GHSR
SAQUINAVIR	4	GHSR
ATAZANAVIR	4	GHSR
PONATINIB	4	GHSR
DULOXETINE	4	GHSR
VILANTEROL	4	GHSR
TIOCONAZOLE	4	GHSR
DESERPIDINE	4	GHSR
THIOTHIXENE	4	GHSR
BUCLIZINE	4	GHSR
CINACALCET	4	GHSR
PYRVINIUM	4	GHSR
INDOCYANINE GREEN ACID FORM	4	GHSR
NAFARELIN	4	GHSR
SERTINDOLE	4	GHSR
FEDRATINIB	4	GHSR
CLOFAZIMINE	4	GHSR
ROTIGOTINE	4	GHSR
FLUNITRAZEPAM	4	GHSR
DARIFENACIN	4	GHSR
ATRACURIUM	4	GHSR
NITAZOXANIDE	4	GHSR
PIMOZIDE	4	GHSR
LIOTHYRONINE	4	GHSR
RIFAXIMIN	4	GHSR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GHSR	373	Functional:238, Binding:135

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GHSR	373

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

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)
BEPRIDIL	4	GHSR
DIBUCAINE	4	GHSR
RIMONABANT	4	GHSR
ARIPIPRAZOLE	4	GHSR
IDARUBICIN	4	GHSR
DICYCLOMINE	4	GHSR
SAQUINAVIR	4	GHSR
ATAZANAVIR	4	GHSR
PONATINIB	4	GHSR
DULOXETINE	4	GHSR
VILANTEROL	4	GHSR
TIOCONAZOLE	4	GHSR
DESERPIDINE	4	GHSR
THIOTHIXENE	4	GHSR
BUCLIZINE	4	GHSR
CINACALCET	4	GHSR
PYRVINIUM	4	GHSR
INDOCYANINE GREEN ACID FORM	4	GHSR
NAFARELIN	4	GHSR
SERTINDOLE	4	GHSR
FEDRATINIB	4	GHSR
CLOFAZIMINE	4	GHSR
ROTIGOTINE	4	GHSR
FLUNITRAZEPAM	4	GHSR
DARIFENACIN	4	GHSR
ATRACURIUM	4	GHSR
NITAZOXANIDE	4	GHSR
PIMOZIDE	4	GHSR
LIOTHYRONINE	4	GHSR
RIFAXIMIN	4	GHSR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GHSR
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	4	STX16, GNAS-AS1, GNAS, STX16-NPEPL1

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)
STX16	0	—
GNAS-AS1	0	—
GNAS	0	—
STX16-NPEPL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.