Trigonocephaly 2

Summary

Trigonocephaly 2 (MONDO:0013774) is a disease caused by FREM1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: FREM1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 444

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	trigonocephaly 2
Mondo ID	MONDO:0013774
OMIM	614485
UMLS	C3280974
MedGen	482604
GARD	0018559
Is cancer (heuristic)	no

Also known as: FREM1 isolated trigonocephaly · isolated trigonocephaly caused by mutation in FREM1 · TRIGNO2 · trigonocephaly 2 · trigonocephaly type 2

Data availability: 444 ClinVar variants · 4 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 › bone development disease › dysostosis › trigonocephaly › isolated trigonocephaly › trigonocephaly 2

Related subtypes (1): trigonocephaly 1

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

444 retrieved; paginated sample, class counts are floors:

369 uncertain significance, 30 conflicting classifications of pathogenicity, 28 likely pathogenic, 8 likely benign, 8 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
30763	NM_001379081.2(FREM1):c.2097_2100del (p.Lys699fs)	FREM1	Pathogenic	criteria provided, multiple submitters, no conflicts
2181765	NM_001379081.2(FREM1):c.6139-2A>G	FREM1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2875317	NM_001379081.2(FREM1):c.3840-2A>G	FREM1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3356066	NM_001379081.2(FREM1):c.5205-1G>A	FREM1	Likely pathogenic	criteria provided, single submitter
3596967	NM_001379081.2(FREM1):c.6139-2A>C	FREM1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3596968	NM_001379081.2(FREM1):c.6122G>A (p.Trp2041Ter)	FREM1	Likely pathogenic	criteria provided, single submitter
3596969	NM_001379081.2(FREM1):c.6105_6121delinsA (p.Ile2036fs)	FREM1	Likely pathogenic	criteria provided, single submitter
3596974	NM_001379081.2(FREM1):c.5925_5928del (p.Gln1976fs)	FREM1	Likely pathogenic	criteria provided, single submitter
3596978	NM_001379081.2(FREM1):c.5845-2A>C	FREM1	Likely pathogenic	criteria provided, single submitter
3596982	NM_001379081.2(FREM1):c.5761C>T (p.Gln1921Ter)	FREM1	Likely pathogenic	criteria provided, single submitter
3597020	NM_001379081.2(FREM1):c.4857+1G>A	FREM1	Likely pathogenic	criteria provided, single submitter
3597029	NM_001379081.2(FREM1):c.4552del (p.Ala1518fs)	FREM1	Likely pathogenic	criteria provided, single submitter
3597039	NM_001379081.2(FREM1):c.4200del (p.Lys1400fs)	FREM1	Likely pathogenic	criteria provided, single submitter
3597046	NM_001379081.2(FREM1):c.4027C>T (p.Gln1343Ter)	FREM1	Likely pathogenic	criteria provided, single submitter
3597061	NM_001379081.2(FREM1):c.3758T>A (p.Leu1253Ter)	FREM1	Likely pathogenic	criteria provided, single submitter
3597065	NM_001379081.2(FREM1):c.3747dup (p.Thr1250fs)	FREM1	Likely pathogenic	criteria provided, single submitter
3597096	NM_001379081.2(FREM1):c.3274+1G>A	FREM1	Likely pathogenic	criteria provided, single submitter
3597113	NM_001379081.2(FREM1):c.2883C>G (p.Tyr961Ter)	FREM1	Likely pathogenic	criteria provided, single submitter
3597119	NM_001379081.2(FREM1):c.2827_2828delinsT (p.Ala942_Gly943insTer)	FREM1	Likely pathogenic	criteria provided, single submitter
3597150	NM_001379081.2(FREM1):c.2212C>T (p.Gln738Ter)	FREM1	Likely pathogenic	criteria provided, single submitter
3597155	NM_001379081.2(FREM1):c.2079-1G>T	FREM1	Likely pathogenic	criteria provided, single submitter
3597163	NM_001379081.2(FREM1):c.1934del (p.Pro645fs)	FREM1	Likely pathogenic	criteria provided, single submitter
3597165	NM_001379081.2(FREM1):c.1912dup (p.Asp638fs)	FREM1	Likely pathogenic	criteria provided, single submitter
3597172	NM_001379081.2(FREM1):c.1649_1650dup (p.Asp551fs)	FREM1	Likely pathogenic	criteria provided, single submitter
3597176	NM_001379081.2(FREM1):c.1441del (p.Val481fs)	FREM1	Likely pathogenic	criteria provided, single submitter
3597185	NM_001379081.2(FREM1):c.1261+1G>T	FREM1	Likely pathogenic	criteria provided, single submitter
3597206	NM_001379081.2(FREM1):c.508G>T (p.Glu170Ter)	FREM1	Likely pathogenic	criteria provided, single submitter
425453	NM_001379081.2(FREM1):c.5205-1G>T	FREM1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3597127	NM_001379081.2(FREM1):c.2687del (p.Met896fs)	LOC126860582	Likely pathogenic	criteria provided, single submitter
1176898	NM_001379081.2(FREM1):c.3274+4A>G	FREM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 4 · 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
FREM1	Strong	Autosomal dominant	trigonocephaly 2	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FREM1	Orphanet:217266	BNAR syndrome
FREM1	Orphanet:2717	Oculotrichoanal syndrome
FREM1	Orphanet:3366	Non-syndromic metopic craniosynostosis
FREM1	Orphanet:93100	Renal agenesis, unilateral

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
FREM1	HGNC:23399	ENSG00000164946	Q5H8C1	FRAS1-related extracellular matrix protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FREM1	FRAS1-related extracellular matrix protein 1	Extracellular matrix protein that plays a role in epidermal differentiation and is required for epidermal adhesion during embryonic development.

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)
FREM1	Other/Unknown	no		C-type_lectin-like, Calx_beta, C-type_lectin-like/link_sf

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
kidney epithelium	1
metanephros	1
smooth muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FREM1	171	broad	marker	kidney epithelium, smooth muscle tissue, metanephros

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FREM1	1,541

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FREM1	Q5H8C1	75.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
craniofacial suture morphogenesis	1	1685.2×	0.002	FREM1
cell communication	1	842.6×	0.002	FREM1
cell-matrix adhesion	1	163.6×	0.007	FREM1
anatomical structure morphogenesis	1	139.3×	0.007	FREM1

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
FREM1	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	FREM1

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)
FREM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.