Trigonocephaly 1

Summary

Trigonocephaly 1 (MONDO:0008603) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 272

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	trigonocephaly 1
Mondo ID	MONDO:0008603
OMIM	190440
UMLS	C0432122
MedGen	98473
GARD	0018558
Is cancer (heuristic)	no

Also known as: FGFR1 isolated trigonocephaly · isolated trigonocephaly caused by mutation in FGFR1 · TRIGNO1 · trigonocephaly 1 · trigonocephaly type 1

Data availability: 272 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › dysostosis › trigonocephaly › isolated trigonocephaly › trigonocephaly 1

Related subtypes (1): trigonocephaly 2

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

272 retrieved; paginated sample, class counts are floors:

141 uncertain significance, 53 conflicting classifications of pathogenicity, 31 benign/likely benign, 20 likely benign, 18 benign, 5 likely pathogenic, 3 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16279	NM_023110.3(FGFR1):c.755C>G (p.Pro252Arg)	FGFR1	Pathogenic	criteria provided, multiple submitters, no conflicts
235087	NM_023110.3(FGFR1):c.1977+1G>A	FGFR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2505415	NM_023110.3(FGFR1):c.710G>A (p.Gly237Asp)	FGFR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
502125	NM_023110.3(FGFR1):c.214C>T (p.Gln72Ter)	FGFR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1338542	NM_023110.3(FGFR1):c.809G>A (p.Gly270Asp)	FGFR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3595591	NM_023110.3(FGFR1):c.1854+2T>C	FGFR1	Likely pathogenic	criteria provided, single submitter
4294512	NM_023110.3(FGFR1):c.104dup (p.Ala36fs)	FGFR1	Likely pathogenic	criteria provided, single submitter
4796553	NM_023110.3(FGFR1):c.2156T>C (p.Met719Thr)	FGFR1	Likely pathogenic	criteria provided, single submitter
654366	NM_023110.3(FGFR1):c.448+1G>A	FGFR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1156684	NM_023110.3(FGFR1):c.789C>T (p.Ala263=)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1186398	NM_023110.3(FGFR1):c.266A>G (p.Gln89Arg)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1197448	NM_023110.3(FGFR1):c.448+1G>C	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1302903	NM_023110.3(FGFR1):c.2428C>T (p.His810Tyr)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1304409	NM_023110.3(FGFR1):c.2426G>A (p.Arg809Gln)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1352087	NM_023110.3(FGFR1):c.169C>A (p.Leu57Met)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1416171	NM_023110.3(FGFR1):c.2267G>A (p.Arg756His)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1431252	NM_023110.3(FGFR1):c.1179G>A (p.Ser393=)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1496164	NM_023110.3(FGFR1):c.346G>A (p.Val116Ile)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1509706	NM_023110.3(FGFR1):c.1186G>A (p.Val396Ile)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
16289	NM_023110.3(FGFR1):c.899T>C (p.Ile300Thr)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
16299	NM_023110.3(FGFR1):c.1097C>T (p.Pro366Leu)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180152	NM_023110.3(FGFR1):c.821A>G (p.Glu274Gly)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2013252	NM_023110.3(FGFR1):c.2107G>A (p.Gly703Ser)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2498226	NM_023110.3(FGFR1):c.*1111C>T	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286846	NM_023110.3(FGFR1):c.211G>T (p.Val71Leu)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2922975	NM_023110.3(FGFR1):c.112G>A (p.Val38Met)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2932035	NM_023110.3(FGFR1):c.746-14C>T	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2945458	NM_023110.3(FGFR1):c.2425C>T (p.Arg809Ter)	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362874	NM_023110.3(FGFR1):c.*1026T>C	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
362883	NM_023110.3(FGFR1):c.*494A>G	FGFR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 17 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGFR1	Orphanet:168953	Myeloid/lymphoid neoplasm associated with FGFR1 rearrangement
FGFR1	Orphanet:2117	Hartsfield syndrome
FGFR1	Orphanet:220386	Semilobar holoprosencephaly
FGFR1	Orphanet:2396	Encephalocraniocutaneous lipomatosis
FGFR1	Orphanet:251576	Gliosarcoma
FGFR1	Orphanet:251579	Giant cell glioblastoma
FGFR1	Orphanet:251615	Pilomyxoid astrocytoma
FGFR1	Orphanet:2645	Osteoglosphonic dysplasia
FGFR1	Orphanet:280200	Microform holoprosencephaly
FGFR1	Orphanet:314950	Primary hypereosinophilic syndrome
FGFR1	Orphanet:3157	Septo-optic dysplasia spectrum
FGFR1	Orphanet:3366	Non-syndromic metopic craniosynostosis
FGFR1	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
FGFR1	Orphanet:478	Kallmann syndrome
FGFR1	Orphanet:93258	Pfeiffer syndrome type 1
FGFR1	Orphanet:93924	Lobar holoprosencephaly
FGFR1	Orphanet:99798	Oligodontia

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
FGFR1	HGNC:3688	ENSG00000077782	P11362	Fibroblast growth factor receptor 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGFR1	Fibroblast growth factor receptor 1	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FGFR1	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2

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
buccal mucosa cell	1
calcaneal tendon	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGFR1	292	ubiquitous	marker	buccal mucosa cell, stromal cell of endometrium, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGFR1	5,693

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGFR1	P11362	83

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. 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
Signaling by FGFR1 amplification mutants	1	5710.0×	0.003	FGFR1
FGFR1c and Klotho ligand binding and activation	1	2855.0×	0.003	FGFR1
Signaling by plasma membrane FGFR1 fusions	1	2855.0×	0.003	FGFR1
Epithelial-Mesenchymal Transition (EMT) during gastrulation	1	1427.5×	0.003	FGFR1
FGFR1b ligand binding and activation	1	1268.9×	0.003	FGFR1
Signaling by activated point mutants of FGFR1	1	951.7×	0.004	FGFR1
FGFR1c ligand binding and activation	1	761.3×	0.004	FGFR1
Phospholipase C-mediated cascade: FGFR1	1	671.8×	0.004	FGFR1
Downstream signaling of activated FGFR1	1	543.8×	0.004	FGFR1
Signal transduction by L1	1	519.1×	0.004	FGFR1
PI-3K cascade:FGFR1	1	519.1×	0.004	FGFR1
SHC-mediated cascade:FGFR1	1	496.5×	0.004	FGFR1
FRS-mediated FGFR1 signaling	1	456.8×	0.004	FGFR1
Formation of paraxial mesoderm	1	407.9×	0.004	FGFR1
Negative regulation of FGFR1 signaling	1	368.4×	0.004	FGFR1
Signaling by FGFR1 in disease	1	292.8×	0.004	FGFR1
PI3K Cascade	1	271.9×	0.004	FGFR1
NCAM signaling for neurite out-growth	1	271.9×	0.004	FGFR1
Constitutive Signaling by Aberrant PI3K in Cancer	1	126.9×	0.009	FGFR1
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	96.8×	0.011	FGFR1
PIP3 activates AKT signaling	1	66.8×	0.016	FGFR1
RAF/MAP kinase cascade	1	61.1×	0.016	FGFR1

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
vitamin D3 metabolic process	1	8426.0×	0.002	FGFR1
positive regulation of mitotic cell cycle DNA replication	1	8426.0×	0.002	FGFR1
positive regulation of parathyroid hormone secretion	1	8426.0×	0.002	FGFR1
regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	8426.0×	0.002	FGFR1
regulation of phosphate transport	1	5617.3×	0.002	FGFR1
fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development	1	5617.3×	0.002	FGFR1
regulation of lateral mesodermal cell fate specification	1	5617.3×	0.002	FGFR1
ventricular zone neuroblast division	1	4213.0×	0.002	FGFR1
negative regulation of fibroblast growth factor production	1	4213.0×	0.002	FGFR1
positive regulation of phospholipase activity	1	3370.4×	0.002	FGFR1
regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling	1	3370.4×	0.002	FGFR1
diphosphate metabolic process	1	3370.4×	0.002	FGFR1
chordate embryonic development	1	2808.7×	0.002	FGFR1
positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway	1	2808.7×	0.002	FGFR1
cementum mineralization	1	2407.4×	0.002	FGFR1
auditory receptor cell development	1	1872.4×	0.002	FGFR1
paraxial mesoderm development	1	1685.2×	0.002	FGFR1
lung-associated mesenchyme development	1	1685.2×	0.002	FGFR1
response to sodium phosphate	1	1685.2×	0.002	FGFR1
outer ear morphogenesis	1	1532.0×	0.002	FGFR1
branching involved in salivary gland morphogenesis	1	1404.3×	0.002	FGFR1
organ induction	1	1203.7×	0.003	FGFR1
mesenchymal cell proliferation	1	1123.5×	0.003	FGFR1
positive regulation of endothelial cell chemotaxis	1	991.3×	0.003	FGFR1
cell projection assembly	1	936.2×	0.003	FGFR1
regulation of postsynaptic density assembly	1	887.0×	0.003	FGFR1
positive regulation of vascular endothelial cell proliferation	1	842.6×	0.003	FGFR1
middle ear morphogenesis	1	702.2×	0.003	FGFR1
phosphatidylinositol-mediated signaling	1	702.2×	0.003	FGFR1
positive regulation of MAP kinase activity	1	648.1×	0.003	FGFR1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
FGFR1	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR1	93	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	FGFR1
PEMIGATINIB	4	FGFR1
NINTEDANIB	4	FGFR1
FEDRATINIB	4	FGFR1
TIVOZANIB	4	FGFR1
LENVATINIB	4	FGFR1
AXITINIB	4	FGFR1
SORAFENIB	4	FGFR1
NICLOSAMIDE	4	FGFR1
INFIGRATINIB PHOSPHATE	4	FGFR1
INFIGRATINIB	4	FGFR1
REGORAFENIB	4	FGFR1
ENTRECTINIB	4	FGFR1
CABOZANTINIB	4	FGFR1
CAPIVASERTIB	4	FGFR1
VANDETANIB	4	FGFR1
NINTEDANIB ESYLATE	4	FGFR1
BRIGATINIB	4	FGFR1
ERDAFITINIB	4	FGFR1
UPADACITINIB	4	FGFR1
FUTIBATINIB	4	FGFR1
PAZOPANIB	4	FGFR1
SUNITINIB	4	FGFR1
DASATINIB	4	FGFR1
MIDOSTAURIN	4	FGFR1
LINIFANIB	3	FGFR1
SEMAXANIB	3	FGFR1
OLVEREMBATINIB	3	FGFR1
BRIVANIB ALANINATE	3	FGFR1
ORANTINIB	3	FGFR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
FGFR1	1,465	Binding:1428, Functional:24, ADMET:13

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FGFR1	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
FGFR1	1,465

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

30 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.

Compound	Max phase	Cohort target (bioactivity)
PONATINIB	4	FGFR1
PEMIGATINIB	4	FGFR1
NINTEDANIB	4	FGFR1
FEDRATINIB	4	FGFR1
TIVOZANIB	4	FGFR1
LENVATINIB	4	FGFR1
AXITINIB	4	FGFR1
SORAFENIB	4	FGFR1
NICLOSAMIDE	4	FGFR1
INFIGRATINIB PHOSPHATE	4	FGFR1
INFIGRATINIB	4	FGFR1
REGORAFENIB	4	FGFR1
ENTRECTINIB	4	FGFR1
CABOZANTINIB	4	FGFR1
CAPIVASERTIB	4	FGFR1
VANDETANIB	4	FGFR1
NINTEDANIB ESYLATE	4	FGFR1
BRIGATINIB	4	FGFR1
ERDAFITINIB	4	FGFR1
UPADACITINIB	4	FGFR1
FUTIBATINIB	4	FGFR1
PAZOPANIB	4	FGFR1
SUNITINIB	4	FGFR1
DASATINIB	4	FGFR1
MIDOSTAURIN	4	FGFR1
LINIFANIB	3	FGFR1
SEMAXANIB	3	FGFR1
OLVEREMBATINIB	3	FGFR1
BRIVANIB ALANINATE	3	FGFR1
ORANTINIB	3	FGFR1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	FGFR1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.