Progressive osseous heteroplasia

Summary

Progressive osseous heteroplasia (MONDO:0008153) is a disease caused by GNAS (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GNAS (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 92
• Phenotypes (HPO): 12
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		78	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0001376	Limitation of joint mobility	Very frequent (80-99%)
HP:0001482	Subcutaneous nodule	Very frequent (80-99%)
HP:0002653	Bone pain	Very frequent (80-99%)
HP:0010766	Ectopic calcification	Very frequent (80-99%)
HP:0011987	Ectopic ossification in muscle tissue	Frequent (30-79%)
HP:0000828	Abnormality of the parathyroid gland	Occasional (5-29%)
HP:0001034	Hypermelanotic macule	Occasional (5-29%)
HP:0001156	Brachydactyly	Occasional (5-29%)
HP:0002758	Osteoarthritis	Occasional (5-29%)
HP:0012733	Macule	Occasional (5-29%)
HP:0100242	Sarcoma	Occasional (5-29%)
HP:0200034	Papule	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive osseous heteroplasia
Mondo ID	MONDO:0008153
MeSH	C562735
OMIM	166350
Orphanet	2762
DOID	DOID:0111535
ICD-11	1107209347
SNOMED CT	719271000
UMLS	C0334041
MedGen	137714
GARD	0000109
MedDRA	10048902
NORD	1618
Is cancer (heuristic)	no

Also known as: ectopic ossification familial type · familial ectopic ossification · osseous heteroplasia, progressive · POH · poh

Data availability: 92 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › dermis disorder › progressive osseous heteroplasia

Related subtypes (27): dermis tumor, necrobiosis lipoidica, isolated anhidrosis with normal sweat glands, familial cutaneous collagenoma, elastosis perforans serpiginosa, antecubital pterygium syndrome, familial reactive perforating collagenosis, dermochondrocorneal dystrophy, lipoid proteinosis, primary cutaneous amyloidosis, linear atrophoderma of Moulin, confetti-like macular atrophy, late-onset focal dermal elastosis, linear focal dermal elastosis, elastoderma, elastoma, papular elastorrhexis, primary anetoderma, familial anetoderma, white fibrous papulosis of the neck, mid-dermal elastolysis, lichen myxedematosus, pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa, primary cutis verticis gyrata, mixed dermis disorder, atrophoderma of Pierini and Pasini, annular erythema of infancy

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

92 retrieved; paginated sample, class counts are floors:

31 uncertain significance, 22 likely benign, 12 pathogenic, 10 benign/likely benign, 5 conflicting classifications of pathogenicity, 5 pathogenic/likely pathogenic, 4 likely pathogenic, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1217738	NM_000516.7(GNAS):c.91C>T (p.Gln31Ter)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
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
15927	NM_000516.7(GNAS):c.1A>G (p.Met1Val)	GNAS	Pathogenic	criteria provided, multiple submitters, no conflicts
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
15951	NM_000516.7(GNAS):c.860_861del (p.Val287fs)	GNAS	Pathogenic	criteria provided, single submitter
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
3376647	NM_000516.7(GNAS):c.153del (p.Gly52fs)	GNAS	Pathogenic	criteria provided, single submitter
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
1333670	NM_000516.7(GNAS):c.880dup (p.Gln294fs)	GNAS	Likely pathogenic	criteria provided, single submitter
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
4530643	NM_000516.7(GNAS):c.236del (p.Ala79fs)	GNAS	Likely pathogenic	no assertion criteria provided
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
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
931358	NM_080425.4(GNAS):c.1276G>C (p.Ala426Pro)	GNAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1048823	NM_080425.4(GNAS):c.538C>T (p.Gln180Ter)	GNAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1098700	NM_080425.4(GNAS):c.1130G>T (p.Gly377Val)	GNAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1215279	NM_000516.7(GNAS):c.985G>A (p.Gly329Arg)	GNAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1315968	NM_080425.4(GNAS):c.1275C>T (p.Phe425=)	GNAS	Uncertain significance	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	progressive osseous heteroplasia	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

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GNAS	HGNC:4392	ENSG00000087460	O95467	Neuroendocrine secretory protein 55	gencc,clinvar

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

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

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 46	1
postcentral gyrus	1
type B pancreatic cell	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNAS	410

Structural data

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

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 1 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: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	GNAS

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)
GNAS	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
NCT04214873	Not specified	COMPLETED	Evaluation of the Effectiveness of the PiQo4 System for Reduction of Infra-orbital Pigmentation