Geleophysic dysplasia 2

Summary

Geleophysic dysplasia 2 (MONDO:0013612) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 330

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	geleophysic dysplasia 2
Mondo ID	MONDO:0013612
OMIM	614185
DOID	DOID:0111726
UMLS	C3280054
MedGen	481684
GARD	0015768
Is cancer (heuristic)	no

Also known as: FBN1 geleophysic dysplasia · Geleophysic dysplasia 2 · geleophysic dysplasia caused by mutation in FBN1 · Geleophysic dysplasia type 2 · GPHYSD2

Data availability: 330 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › acromelic dysplasia › geleophysic dysplasia › geleophysic dysplasia 2

Related subtypes (2): geleophysic dysplasia 1, geleophysic dysplasia 3

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

330 retrieved; paginated sample, class counts are floors:

134 uncertain significance, 121 conflicting classifications of pathogenicity, 25 pathogenic/likely pathogenic, 21 pathogenic, 13 likely benign, 9 likely pathogenic, 4 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1451231	NM_000138.5(FBN1):c.4121G>A (p.Cys1374Tyr)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
163462	NM_000138.5(FBN1):c.7754T>C (p.Ile2585Thr)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
163480	NM_000138.5(FBN1):c.1879C>T (p.Arg627Cys)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
16440	NM_000138.5(FBN1):c.364C>T (p.Arg122Cys)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
16461	NM_000138.5(FBN1):c.718C>T (p.Arg240Cys)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1675081	NM_000138.5(FBN1):c.5836del (p.Gln1946fs)	FBN1	Pathogenic	criteria provided, single submitter
1707834	NM_000138.5(FBN1):c.2753del (p.Pro918fs)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
180351	NM_000138.5(FBN1):c.1285C>T (p.Arg429Ter)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180352	NM_000138.5(FBN1):c.1633C>T (p.Arg545Cys)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1810233	NM_000138.5(FBN1):c.3350G>T (p.Cys1117Phe)	FBN1	Pathogenic	criteria provided, single submitter
200001	NM_000138.5(FBN1):c.2645C>T (p.Ala882Val)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
200022	NM_000138.5(FBN1):c.3712G>A (p.Asp1238Asn)	FBN1	Pathogenic	reviewed by expert panel
200036	NM_000138.5(FBN1):c.4096G>A (p.Glu1366Lys)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
200052	NM_000138.5(FBN1):c.4621C>T (p.Arg1541Ter)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
200191	NM_000138.5(FBN1):c.6388G>A (p.Glu2130Lys)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265401	NM_000138.5(FBN1):c.2581C>T (p.Arg861Ter)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2925582	NM_000138.5(FBN1):c.407G>T (p.Cys136Phe)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29696	NM_000138.5(FBN1):c.5096A>G (p.Tyr1699Cys)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
29697	NM_000138.5(FBN1):c.5284G>A (p.Gly1762Ser)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
29698	NM_000138.5(FBN1):c.5182G>A (p.Ala1728Thr)	FBN1	Pathogenic	no assertion criteria provided
29699	NM_000138.5(FBN1):c.5087A>G (p.Tyr1696Cys)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36042	NM_000138.5(FBN1):c.1948C>T (p.Arg650Cys)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36075	NM_000138.5(FBN1):c.4460-8G>A	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36078	NM_000138.5(FBN1):c.4588C>T (p.Arg1530Cys)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36082	NM_000138.5(FBN1):c.4786C>T (p.Arg1596Ter)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
36107	NM_000138.5(FBN1):c.6806T>C (p.Ile2269Thr)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
42284	NM_000138.5(FBN1):c.1468+5G>A	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
42295	NM_000138.5(FBN1):c.184C>T (p.Arg62Cys)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
42340	NM_000138.5(FBN1):c.368G>A (p.Cys123Tyr)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
42351	NM_000138.5(FBN1):c.4222T>C (p.Cys1408Arg)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FBN1	Orphanet:1885	Isolated ectopia lentis
FBN1	Orphanet:2084	Glaucoma-ectopia lentis-microspherophakia-stiff joints-short stature syndrome
FBN1	Orphanet:2462	Shprintzen-Goldberg syndrome
FBN1	Orphanet:2623	Geleophysic dysplasia
FBN1	Orphanet:2833	Stiff skin syndrome
FBN1	Orphanet:284963	Marfan syndrome type 1
FBN1	Orphanet:284979	Neonatal Marfan syndrome
FBN1	Orphanet:300382	Progeroid and marfanoid aspect-lipodystrophy syndrome
FBN1	Orphanet:3449	Weill-Marchesani syndrome
FBN1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
FBN1	Orphanet:969	Acromicric dysplasia

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
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FBN1	Fibrillin-1	Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues.

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)
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

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
decidua	1
skin of hip	1
synovial joint	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FBN1	275	ubiquitous	marker	synovial joint, skin of hip, decidua

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBN1	3,640

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FBN1	P35555	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Elastic fibre formation	1	335.9×	0.008	FBN1
TGF-beta receptor signaling activates SMADs	1	326.3×	0.008	FBN1
Molecules associated with elastic fibres	1	308.6×	0.008	FBN1
Integrin cell surface interactions	1	134.3×	0.012	FBN1
Degradation of the extracellular matrix	1	117.7×	0.012	FBN1
Post-translational protein phosphorylation	1	100.2×	0.012	FBN1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	FBN1

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
post-embryonic eye morphogenesis	1	5617.3×	0.001	FBN1
obsolete sequestering of BMP in extracellular matrix	1	4213.0×	0.001	FBN1
obsolete sequestering of TGFbeta in extracellular matrix	1	4213.0×	0.001	FBN1
negative regulation of osteoclast development	1	3370.4×	0.001	FBN1
embryonic eye morphogenesis	1	1532.0×	0.002	FBN1
cellular response to insulin-like growth factor stimulus	1	1296.3×	0.002	FBN1
cell adhesion mediated by integrin	1	674.1×	0.004	FBN1
negative regulation of osteoclast differentiation	1	543.6×	0.004	FBN1
metanephros development	1	510.7×	0.004	FBN1
camera-type eye development	1	358.6×	0.004	FBN1
lung alveolus development	1	351.1×	0.004	FBN1
cellular response to transforming growth factor beta stimulus	1	276.3×	0.005	FBN1
glucose metabolic process	1	255.3×	0.005	FBN1
glucose homeostasis	1	130.6×	0.009	FBN1
skeletal system development	1	125.8×	0.009	FBN1
gene expression	1	79.9×	0.013	FBN1
heart development	1	78.8×	0.013	FBN1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FBN1	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	FBN1

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)
FBN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.