pseudohypoparathyroidism type 1C

Summary

pseudohypoparathyroidism type 1C (MONDO:0012911) is a disease caused by GNAS (GenCC Strong), with 4 cohort genes and 1 clinical trial. Top therapeutic interventions include theophylline anhydrous.

At a glance

• Prevalence: Unknown (Europe) [Orphanet-validated]
• Causal gene: GNAS (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 106
• Phenotypes (HPO): 55
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

55 HPO clinical features (Orphanet curated; top 50 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:0008227	Pituitary resistance to thyroid hormone	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: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:0004322	Short stature	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: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:0011986	Ectopic ossification	Frequent (30-79%)
HP:0012185	Constrictive median neuropathy	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:0000815	Hypergonadotropic hypogonadism	Occasional (5-29%)
HP:0000876	Oligomenorrhea	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001289	Confusion	Occasional (5-29%)
HP:0001657	Prolonged QT interval	Occasional (5-29%)
HP:0002094	Dyspnea	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:0009642	Broad distal phalanx of the thumb	Occasional (5-29%)
HP:0010041	Short 3rd metacarpal	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%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pseudohypoparathyroidism type 1C
Mondo ID	MONDO:0012911
MeSH	C548076
OMIM	612462
Orphanet	79444
DOID	DOID:0051013
ICD-11	1401673748
SNOMED CT	717792007
UMLS	C2932716
MedGen	420958
GARD	0010681
Is cancer (heuristic)	no

Also known as: PHP1C · pseudohypoparathyroidism Ic · pseudohypoparathyroidism, type IC

Data availability: 106 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › osteonecrosis › avascular necrosis › primary avascular necrosis › pseudohypoparathyroidism type 1C

Related subtypes (2): familial avascular necrosis of femoral head, idiopathic avascular necrosis

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

106 retrieved; paginated sample, class counts are floors:

40 uncertain significance, 22 likely benign, 14 pathogenic, 10 benign/likely benign, 8 pathogenic/likely pathogenic, 6 conflicting classifications of pathogenicity, 3 likely pathogenic, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4082251	NC_000020.10:g.57331908_60789961del	ATP5F1E	Pathogenic	criteria provided, single submitter
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
1500589	NM_000516.7(GNAS):c.1006C>T (p.Arg336Trp)	GNAS	Pathogenic/Likely 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
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
15959	NM_000516.7(GNAS):c.1173C>R (p.Tyr391Ter)	GNAS	Pathogenic	no assertion criteria provided
1705690	NM_000516.7(GNAS):c.460_461del (p.Trp154fs)	GNAS	Pathogenic	criteria provided, single submitter
209158	NM_000516.7(GNAS):c.34C>T (p.Gln12Ter)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
216937	NM_000516.7(GNAS):c.880C>T (p.Gln294Ter)	GNAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29745	NM_000516.7(GNAS):c.1174G>T (p.Glu392Ter)	GNAS	Pathogenic	no assertion criteria provided
29746	NM_000516.7(GNAS):c.1163T>G (p.Leu388Arg)	GNAS	Pathogenic	no assertion criteria provided
29747	NM_000516.7(GNAS):c.1174G>A (p.Glu392Lys)	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
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
3901267	NC_000020.10:g.55906911_58646228del	STX16	Pathogenic	criteria provided, single submitter
1065524	NM_000516.7(GNAS):c.403_411del (p.Met135_Val137del)	GNAS	Likely pathogenic	no assertion criteria provided
1334571	NM_000516.7(GNAS):c.124dup (p.Arg42fs)	GNAS	Likely pathogenic	criteria provided, single submitter
4057287	NM_000516.7(GNAS):c.1173C>G (p.Tyr391Ter)	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
2963682	NM_000516.7(GNAS):c.585+12C>T	GNAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
689463	NM_000516.7(GNAS):c.137T>G (p.Leu46Arg)	GNAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · 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

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
STX16	Orphanet:94089	Pseudohypoparathyroidism type 1B
ATP5F1E	Orphanet:254913	Isolated ATP synthase deficiency

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GNAS	HGNC:4392	ENSG00000087460	O95467	Neuroendocrine secretory protein 55	gencc,clinvar
STX16	HGNC:11431	ENSG00000124222	O14662	Syntaxin-16	clinvar
GNAS-AS1	HGNC:24872	ENSG00000235590		GNAS antisense RNA 1	clinvar
ATP5F1E	HGNC:838	ENSG00000124172	P56381	ATP synthase F(1) complex subunit epsilon, mitochondrial	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.
ATP5F1E	ATP synthase F(1) complex subunit epsilon, mitochondrial	Subunit epsilon, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GNAS	Other/Unknown	no		NESP55, Gprotein_alpha_S, Gprotein_alpha_su
STX16	Other/Unknown	no		T_SNARE_dom, Syntaxin/epimorphin_CS, SNARE
GNAS-AS1	Other/Unknown	no
ATP5F1E	Other/Unknown	no		ATP_synth_F1_esu_mt, ATP_synth_F1_esu_sf_mt

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 46	1
postcentral gyrus	1
type B pancreatic cell	1
corpus callosum	1
right uterine tube	1
sural nerve	1
cortical plate	1
islet of Langerhans	1
tibia	1
cranial nerve II	1
renal medulla	1
substantia nigra pars reticulata	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
STX16	300	broad	marker	right uterine tube, sural nerve, corpus callosum
GNAS-AS1	148	broad	yes	islet of Langerhans, cortical plate, tibia
ATP5F1E	296	ubiquitous	marker	renal medulla, cranial nerve II, substantia nigra pars reticulata

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STX16	1,793
ATP5F1E	1,742
GNAS	410
GNAS-AS1	0

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAS	O95467	490
ATP5F1E	P56381	10
STX16	O14662	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 4 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
Formation of ATP by chemiosmotic coupling	1	190.3×	0.025	ATP5F1E
Glucagon signaling in metabolic regulation	1	115.3×	0.025	GNAS
Glucagon-type ligand receptors	1	115.3×	0.025	GNAS
Cristae formation	1	115.3×	0.025	ATP5F1E
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
Mitochondrial biogenesis	1	56.0×	0.028	ATP5F1E
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	53.6×	0.028	GNAS
Intra-Golgi and retrograde Golgi-to-ER traffic	1	34.9×	0.040	STX16
Aerobic respiration and respiratory electron transport	1	29.5×	0.045	ATP5F1E
G alpha (s) signalling events	1	24.4×	0.051	GNAS
Organelle biogenesis and maintenance	1	22.0×	0.054	ATP5F1E
G alpha (i) signalling events	1	13.0×	0.086	GNAS
Membrane Trafficking	1	12.4×	0.086	STX16
Vesicle-mediated transport	1	11.6×	0.087	STX16
Metabolism	1	3.9×	0.237	ATP5F1E

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
adenylate cyclase-activating G protein-coupled bile acid receptor signaling pathway	1	1872.4×	0.008	GNAS
response to parathyroid hormone	1	1404.3×	0.008	GNAS
adenylate cyclase-activating serotonin receptor signaling pathway	1	1123.5×	0.008	GNAS
hair follicle placode formation	1	1123.5×	0.008	GNAS
regulation of skeletal muscle contraction	1	936.2×	0.008	GNAS
cellular response to catecholamine stimulus	1	802.5×	0.008	GNAS
adenylate cyclase-activating dopamine receptor signaling pathway	1	510.7×	0.008	GNAS
intracellular transport	1	510.7×	0.008	GNAS
response to prostaglandin E	1	468.1×	0.008	GNAS
adenylate cyclase-activating adrenergic receptor signaling pathway	1	401.2×	0.008	GNAS
activation of adenylate cyclase activity	1	374.5×	0.008	GNAS
sensory perception of chemical stimulus	1	374.5×	0.008	GNAS
negative regulation of multicellular organism growth	1	374.5×	0.008	GNAS
cellular response to glucagon stimulus	1	280.9×	0.008	GNAS
cellular response to prostaglandin E stimulus	1	280.9×	0.008	GNAS
proton motive force-driven ATP synthesis	1	267.5×	0.008	ATP5F1E
obsolete vesicle docking	1	255.3×	0.008	STX16
developmental growth	1	244.2×	0.008	GNAS
cellular response to acidic pH	1	244.2×	0.008	GNAS
vascular endothelial cell response to laminar fluid shear stress	1	244.2×	0.008	GNAS
negative regulation of inflammatory response to antigenic stimulus	1	200.6×	0.009	GNAS
vesicle fusion	1	200.6×	0.009	STX16
intracellular glucose homeostasis	1	193.7×	0.009	GNAS
renal water homeostasis	1	170.2×	0.010	GNAS
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	124.8×	0.013	GNAS
platelet aggregation	1	112.3×	0.014	GNAS
cognition	1	95.2×	0.014	GNAS
bone development	1	92.1×	0.014	GNAS
regulation of signal transduction	1	89.2×	0.014	GNAS
endocytic recycling	1	89.2×	0.014	STX16

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
STX16	0	0
GNAS-AS1	0	0
ATP5F1E	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	4	GNAS, STX16, GNAS-AS1, ATP5F1E

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)
GNAS	0	—
STX16	0	—
GNAS-AS1	0	—
ATP5F1E	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03718403	PHASE4	RECRUITING	Effect of Theophylline in Pseudohypoparathyroidism

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
THEOPHYLLINE ANHYDROUS	4	3