Pseudopseudohypoparathyroidism

Summary

Pseudopseudohypoparathyroidism (MONDO:0012912) is a disease caused by GNAS (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Europe) [Orphanet-validated]
• Causal gene: GNAS (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 131
• Phenotypes (HPO): 18
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000311	Round face	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0009237	Short 5th finger	Frequent (30-79%)
HP:0010044	Short 4th metacarpal	Frequent (30-79%)
HP:0010047	Short 5th metacarpal	Frequent (30-79%)
HP:0010743	Short metatarsal	Frequent (30-79%)
HP:0011986	Ectopic ossification	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001513	Obesity	Occasional (5-29%)
HP:0004180	Short distal phalanx of the 3rd finger	Occasional (5-29%)
HP:0009650	Short distal phalanx of the thumb	Occasional (5-29%)
HP:0025027	Osteoma cutis	Occasional (5-29%)
HP:0002901	Hypocalcemia	Excluded (0%)
HP:0002905	Hyperphosphatemia	Excluded (0%)
HP:0003165	Elevated circulating parathyroid hormone level	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pseudopseudohypoparathyroidism
Mondo ID	MONDO:0012912
MeSH	D011556
OMIM	612463
Orphanet	79445, 665
DOID	DOID:4183
ICD-11	245649135
NCIT	C129722
SNOMED CT	237659007
UMLS	C0033835
MedGen	10995
GARD	0007860
Is cancer (heuristic)	no

Also known as: aho-PPHP syndrome · Albright hereditary osteodystrophy-PPHP syndrome · Normocalcemic pseudohypoparathyroidism (disorder) [ambiguous] · PPHP · pseudo-pseudohypoparathyroidism · Pseudopseudo-hypoparathyroidism · pseudopseudohypoparathyroidism

Data availability: 131 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › acromelic dysplasia › pseudopseudohypoparathyroidism

Related subtypes (17): geleophysic dysplasia, Acromicric dysplasia, pseudohypoparathyroidism type 1A, 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, 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

131 retrieved; paginated sample, class counts are floors:

49 uncertain significance, 22 likely benign, 19 pathogenic, 10 benign/likely benign, 10 likely pathogenic, 9 pathogenic/likely pathogenic, 9 conflicting classifications of pathogenicity, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065893	NM_000516.7(GNAS):c.1057G>A (p.Gly353Arg)	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
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
15928	NM_000516.7(GNAS):c.839+1G>C	GNAS	Pathogenic	no assertion criteria provided
15929	NM_000516.7(GNAS):c.725del (p.Thr242fs)	GNAS	Pathogenic	no assertion criteria provided
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
15940	NM_000516.7(GNAS):c.119_139+17del	GNAS	Pathogenic	no assertion criteria provided
15942	NM_000516.7(GNAS):c.772_773delinsGC (p.Arg258Ala)	GNAS	Pathogenic	no assertion criteria provided
15943	GNAS, GLN170ALA	GNAS	Pathogenic	no assertion criteria provided
15947	NM_000516.7(GNAS):c.617_618del (p.Gly206fs)	GNAS	Pathogenic	no assertion criteria provided
15948	NM_000516.7(GNAS):c.302_303del (p.Glu101fs)	GNAS	Pathogenic	no assertion criteria provided
15950	NM_000516.7(GNAS):c.112del (p.Arg38fs)	GNAS	Pathogenic	no assertion criteria provided
15953	NM_000516.7(GNAS):c.344C>T (p.Pro115Leu)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1704397	NM_000516.7(GNAS):c.1125_1126del (p.Phe376fs)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
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
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
446491	NM_000516.7(GNAS):c.432+1G>A	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
4531299	NM_000516.7(GNAS):c.585+1G>C	GNAS	Pathogenic	criteria provided, single submitter
625528	NM_000516.7(GNAS):c.127CTG[5] (p.Leu46dup)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
987921	NM_000516.5:c.(?-424)(257_?)dup	GNAS	Pathogenic	criteria provided, single submitter
1299647	NM_000516.7(GNAS):c.364C>G (p.Pro122Ala)	GNAS	Likely pathogenic	criteria provided, single submitter
1334503	NM_000516.7(GNAS):c.212+1_212+3del	GNAS	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	Strong	Autosomal dominant	pseudopseudohypoparathyroidism	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: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00209235	Not specified	RECRUITING	Albright Hereditary Osteodystrophy: Natural History, Growth, and Cognitive/Behavioral Assessments