pseudohypoparathyroidism type 1A

Summary

pseudohypoparathyroidism type 1A (MONDO:0007078) is a disease caused by GNAS (GenCC Definitive), with 2 cohort genes and 9 clinical trials. Top therapeutic interventions include theophylline anhydrous and setmelanotide.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: GNAS (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 155
• Phenotypes (HPO): 68
• Clinical trials: 9

Clinical features

Signs & symptoms

Clinical features (HPO)

68 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000852	Pseudohypoparathyroidism	Obligate (100%)
HP:0000311	Round face	Very frequent (80-99%)
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:0004322	Short stature	Very frequent (80-99%)
HP:0008227	Pituitary resistance to thyroid hormone	Very frequent (80-99%)
HP:0000293	Full cheeks	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:0000824	Decreased response to growth hormone stimulation test	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001513	Obesity	Frequent (30-79%)
HP:0002135	Basal ganglia calcification	Frequent (30-79%)
HP:0002591	Polyphagia	Frequent (30-79%)
HP:0002684	Thickened calvaria	Frequent (30-79%)
HP:0004704	Short fifth metatarsal	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0006297	Enamel hypoplasia	Frequent (30-79%)
HP:0006960	Choroid plexus calcification	Frequent (30-79%)
HP:0010027	Broad 1st metacarpal	Frequent (30-79%)
HP:0010044	Short 4th metacarpal	Frequent (30-79%)
HP:0010047	Short 5th metacarpal	Frequent (30-79%)
HP:0010049	Short metacarpal	Frequent (30-79%)
HP:0010743	Short metatarsal	Frequent (30-79%)
HP:0011001	Increased bone mineral density	Frequent (30-79%)
HP:0011986	Ectopic ossification	Frequent (30-79%)
HP:0012185	Constrictive median neuropathy	Frequent (30-79%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0000815	Hypergonadotropic hypogonadism	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0000876	Oligomenorrhea	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001266	Choreoathetosis	Occasional (5-29%)
HP:0001289	Confusion	Occasional (5-29%)
HP:0001657	Prolonged QT interval	Occasional (5-29%)
HP:0002094	Dyspnea	Occasional (5-29%)
HP:0002176	Spinal cord compression	Occasional (5-29%)
HP:0002514	Cerebral calcification	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:0003761	Calcinosis	Occasional (5-29%)
HP:0004305	Involuntary movements	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pseudohypoparathyroidism type 1A
Mondo ID	MONDO:0007078
MeSH	C537045
OMIM	103580
Orphanet	79443
DOID	DOID:0080053
ICD-11	1513156369
NCIT	C129721
SNOMED CT	58833000
UMLS	C3494506
MedGen	488447
GARD	0007486
Is cancer (heuristic)	no

Also known as: AHO · AHO-PHP syndrome Ia · Albright hereditary osteodystrophy · Albright hereditary osteodystrophy with multiple hormone resistance · Albright hereditary osteodystrophy-PHP syndrome Ia · PHP1A · Pseudohypoparathyroidism Ia · Pseudohypoparathyroidism type 1A · Pseudohypoparathyroidism, type IA

Data availability: 155 ClinVar variants · 4 GenCC gene-disease records · 13 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › acromelic dysplasia › pseudohypoparathyroidism type 1A

Related subtypes (17): geleophysic dysplasia, Acromicric dysplasia, Angel-shaped phalango-epiphyseal dysplasia, Myhre syndrome, Leri pleonosteosis, peripheral dysostosis, short-rib thoracic dysplasia 9 with or without polydactyly, terminal osseous dysplasia-pigmentary defects syndrome, intellectual disability-balding-patella luxation-acromicria syndrome, acrocapitofemoral dysplasia, pseudohypoparathyroidism type 1C, pseudopseudohypoparathyroidism, short stature-brachydactyly-obesity-global developmental delay syndrome, trichorhinophalangeal syndrome, Weill-Marchesani syndrome, craniofacial conodysplasia, acrodysostosis

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

155 retrieved; paginated sample, class counts are floors:

48 uncertain significance, 30 pathogenic, 22 likely benign, 16 likely pathogenic, 13 conflicting classifications of pathogenicity, 13 pathogenic/likely pathogenic, 10 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065880	NM_000516.7(GNAS):c.124C>A (p.Arg42Ser)	GNAS	Pathogenic	criteria provided, single submitter
1065881	NM_000516.7(GNAS):c.127C>G (p.Leu43Val)	GNAS	Pathogenic	criteria provided, single submitter
1065882	NM_000516.7(GNAS):c.1150C>G (p.Gln384Glu)	GNAS	Pathogenic	criteria provided, single submitter
1065883	NM_000516.7(GNAS):c.489C>G (p.Tyr163Ter)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1065884	NM_000516.7(GNAS):c.507C>A (p.Tyr169Ter)	GNAS	Pathogenic	criteria provided, single submitter
1065885	NM_000516.7(GNAS):c.595C>T (p.Arg199Cys)	GNAS	Pathogenic	criteria provided, single submitter
1065886	NM_000516.7(GNAS):c.682C>T (p.Arg228Cys)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1065888	NM_000516.7(GNAS):c.773G>T (p.Arg258Leu)	GNAS	Pathogenic	criteria provided, single submitter
1065889	NM_000516.7(GNAS):c.794G>A (p.Arg265His)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065890	NM_000516.7(GNAS):c.917C>T (p.Ser306Leu)	GNAS	Pathogenic	criteria provided, single submitter
1065891	NM_000516.7(GNAS):c.1025G>A (p.Arg342Gln)	GNAS	Pathogenic	criteria provided, single submitter
1065892	NM_000516.7(GNAS):c.1040G>C (p.Arg347Thr)	GNAS	Pathogenic	criteria provided, single submitter
1065893	NM_000516.7(GNAS):c.1057G>A (p.Gly353Arg)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065894	NM_000516.7(GNAS):c.1067G>A (p.Arg356His)	GNAS	Pathogenic	criteria provided, single submitter
1065895	NM_000516.7(GNAS):c.1115T>C (p.Ile372Thr)	GNAS	Pathogenic	criteria provided, single submitter
1191792	NM_000516.7(GNAS):c.518_521del (p.Asp173fs)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1217738	NM_000516.7(GNAS):c.91C>T (p.Gln31Ter)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1332852	NM_000516.7(GNAS):c.3G>T (p.Met1Ile)	GNAS	Pathogenic	criteria provided, single submitter
1354948	NM_000516.7(GNAS):c.348del (p.Val117fs)	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
1500589	NM_000516.7(GNAS):c.1006C>T (p.Arg336Trp)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15932	NM_000516.7(GNAS):c.493C>T (p.Arg165Cys)	GNAS	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
15946	NM_000516.7(GNAS):c.692G>A (p.Arg231His)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1685855	NM_000516.7(GNAS):c.596G>C (p.Arg199Pro)	GNAS	Pathogenic	criteria provided, single submitter
1685856	NM_000516.7(GNAS):c.602dup (p.Val202fs)	GNAS	Pathogenic	criteria provided, single submitter
1692997	NM_000516.7(GNAS):c.719-29_719-13delinsACCAAAGAGAGCAAAGCCAAG	GNAS	Pathogenic	no assertion criteria provided
209158	NM_000516.7(GNAS):c.34C>T (p.Gln12Ter)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
2138359	NM_000516.7(GNAS):c.308T>C (p.Ile103Thr)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · 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
GNAS	Definitive	Autosomal dominant	pseudohypoparathyroidism type 1A	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GNAS	HGNC:4392	ENSG00000087460	O95467	Neuroendocrine secretory protein 55	gencc,clinvar
GNAS-AS1	HGNC:24872	ENSG00000235590		GNAS antisense RNA 1	clinvar

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GNAS	Other/Unknown	no		NESP55, Gprotein_alpha_S, Gprotein_alpha_su
GNAS-AS1	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 46	1
postcentral gyrus	1
type B pancreatic cell	1
cortical plate	1
islet of Langerhans	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNAS	312	ubiquitous	marker	type B pancreatic cell, postcentral gyrus, Brodmann (1909) area 46
GNAS-AS1	148	broad	yes	islet of Langerhans, cortical plate, tibia

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNAS	410
GNAS-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAS	O95467	490

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 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
PKA activation in glucagon signalling	1	671.8×	0.006	GNAS
Prostacyclin signalling through prostacyclin receptor	1	601.0×	0.006	GNAS
Glucagon signaling in metabolic regulation	1	346.1×	0.006	GNAS
Glucagon-type ligand receptors	1	346.1×	0.006	GNAS
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	265.6×	0.006	GNAS
Vasopressin regulates renal water homeostasis via Aquaporins	1	265.6×	0.006	GNAS
ADORA2B mediated anti-inflammatory cytokines production	1	253.8×	0.006	GNAS
GPER1 signaling	1	248.3×	0.006	GNAS
G alpha (z) signalling events	1	233.1×	0.006	GNAS
Hedgehog ‘off’ state	1	178.4×	0.007	GNAS
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	160.8×	0.007	GNAS
G alpha (s) signalling events	1	73.2×	0.015	GNAS
G alpha (i) signalling events	1	39.0×	0.026	GNAS

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
adenylate cyclase-activating G protein-coupled bile acid receptor signaling pathway	1	5617.3×	0.002	GNAS
response to parathyroid hormone	1	4213.0×	0.002	GNAS
adenylate cyclase-activating serotonin receptor signaling pathway	1	3370.4×	0.002	GNAS
hair follicle placode formation	1	3370.4×	0.002	GNAS
regulation of skeletal muscle contraction	1	2808.7×	0.002	GNAS
cellular response to catecholamine stimulus	1	2407.4×	0.002	GNAS
adenylate cyclase-activating dopamine receptor signaling pathway	1	1532.0×	0.002	GNAS
intracellular transport	1	1532.0×	0.002	GNAS
response to prostaglandin E	1	1404.3×	0.002	GNAS
adenylate cyclase-activating adrenergic receptor signaling pathway	1	1203.7×	0.002	GNAS
activation of adenylate cyclase activity	1	1123.5×	0.002	GNAS
sensory perception of chemical stimulus	1	1123.5×	0.002	GNAS
negative regulation of multicellular organism growth	1	1123.5×	0.002	GNAS
cellular response to glucagon stimulus	1	842.6×	0.003	GNAS
cellular response to prostaglandin E stimulus	1	842.6×	0.003	GNAS
developmental growth	1	732.7×	0.003	GNAS
cellular response to acidic pH	1	732.7×	0.003	GNAS
vascular endothelial cell response to laminar fluid shear stress	1	732.7×	0.003	GNAS
negative regulation of inflammatory response to antigenic stimulus	1	601.9×	0.003	GNAS
intracellular glucose homeostasis	1	581.1×	0.003	GNAS
renal water homeostasis	1	510.7×	0.003	GNAS
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	374.5×	0.004	GNAS
platelet aggregation	1	337.0×	0.004	GNAS
cognition	1	285.6×	0.005	GNAS
bone development	1	276.3×	0.005	GNAS
regulation of signal transduction	1	267.5×	0.005	GNAS
protein secretion	1	263.3×	0.005	GNAS
positive regulation of insulin secretion	1	255.3×	0.005	GNAS
female pregnancy	1	210.7×	0.005	GNAS
positive regulation of cold-induced thermogenesis	1	163.6×	0.007	GNAS

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 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
GNAS	0	0
GNAS-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	GNAS, GNAS-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GNAS	0	—
GNAS-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	5
Not specified	4

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03029429	PHASE2	ACTIVE_NOT_RECRUITING	Theophylline Treatment for Pseudohypoparathyroidism
NCT04240821	PHASE2	ENROLLING_BY_INVITATION	Theophylline for Treatment of Pseudohypoparathyroidism
NCT04551170	PHASE2	ACTIVE_NOT_RECRUITING	Theophylline Treatment for Pseudohypoparathyroidism - Children 2-12 Years Old
NCT07496463	PHASE2	NOT_YET_RECRUITING	Setmelanotide to Treat Obesity in a Patient With Pseudohypoparathyroidism Type 1a (PHP1a)
NCT02463409	PHASE2	COMPLETED	Theophylline as a Treatment for Children With Pseudohypoparathyroidism Type 1a (Albright Hereditary Osteodystrophy)
NCT00209235	Not specified	RECRUITING	Albright Hereditary Osteodystrophy: Natural History, Growth, and Cognitive/Behavioral Assessments
NCT01398774	Not specified	TERMINATED	Energy Expenditure and Body Composition in Pseudohypoparathyroidism 1a
NCT02411461	Not specified	COMPLETED	Early-onset Obesity and Cognitive Impairment in Children With Pseudohypoparathyroidism
NCT03761290	Not specified	TERMINATED	Glucose Homeostasis in Pseudohypoparathyroidism

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
THEOPHYLLINE ANHYDROUS	4	9
SETMELANOTIDE	4	1
CHEMBL4067491	0	1