Spondylometaphyseal dysplasia, 'corner fracture' type

Summary

Spondylometaphyseal dysplasia, ‘corner fracture’ type (MONDO:0008479) is a disease caused by FN1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FN1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 457
• Phenotypes (HPO): 54

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

54 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0002812	Coxa vara	Very frequent (80-99%)
HP:0003025	Metaphyseal irregularity	Very frequent (80-99%)
HP:0003300	Ovoid vertebral bodies	Very frequent (80-99%)
HP:0003468	Abnormal vertebral morphology	Very frequent (80-99%)
HP:0003908	Corner fracture of metaphysis	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0000768	Pectus carinatum	Frequent (30-79%)
HP:0001376	Limitation of joint mobility	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002857	Genu valgum	Frequent (30-79%)
HP:0002970	Genu varum	Frequent (30-79%)
HP:0003026	Short long bone	Frequent (30-79%)
HP:0003521	Disproportionate short-trunk short stature	Frequent (30-79%)
HP:0006385	Short lower limbs	Frequent (30-79%)
HP:0009763	Limb pain	Frequent (30-79%)
HP:0009824	Upper limb undergrowth	Frequent (30-79%)
HP:0011849	Abnormal bone ossification	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000307	Pointed chin	Occasional (5-29%)
HP:0000324	Facial asymmetry	Occasional (5-29%)
HP:0000358	Posteriorly rotated ears	Occasional (5-29%)
HP:0000384	Preauricular skin tag	Occasional (5-29%)
HP:0000385	Small earlobe	Occasional (5-29%)
HP:0000411	Protruding ear	Occasional (5-29%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0000520	Proptosis	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000926	Platyspondyly	Occasional (5-29%)
HP:0002938	Lumbar hyperlordosis	Occasional (5-29%)
HP:0002945	Intervertebral space narrowing	Occasional (5-29%)
HP:0002948	Vertebral fusion	Occasional (5-29%)
HP:0002982	Tibial bowing	Occasional (5-29%)
HP:0004586	Biconcave vertebral bodies	Occasional (5-29%)
HP:0004625	Biconvex vertebral bodies	Occasional (5-29%)
HP:0008417	Vertebral hypoplasia	Occasional (5-29%)
HP:0008422	Vertebral wedging	Occasional (5-29%)
HP:0008577	Underfolded helix	Occasional (5-29%)
HP:0009896	Abnormality of the antitragus	Occasional (5-29%)
HP:0012368	Flat face	Occasional (5-29%)
HP:0100559	Lower limb asymmetry	Occasional (5-29%)
HP:0000164	Abnormality of the dentition	Very rare (<1-4%)
HP:0000470	Short neck	Very rare (<1-4%)
HP:0000486	Strabismus	Very rare (<1-4%)
HP:0001891	Iron deficiency anemia	Very rare (<1-4%)
HP:0002659	Increased susceptibility to fractures	Very rare (<1-4%)
HP:0002866	Hypoplastic iliac wing	Very rare (<1-4%)
HP:0004349	Reduced bone mineral density	Very rare (<1-4%)
HP:0005743	Avascular necrosis of the capital femoral epiphysis	Very rare (<1-4%)
HP:0007906	Ocular hypertension	Very rare (<1-4%)
HP:0008440	C1-C2 vertebral abnormality	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spondylometaphyseal dysplasia, ‘corner fracture’ type
Mondo ID	MONDO:0008479
MeSH	C535793
OMIM	184255
Orphanet	93315
DOID	DOID:0112297
ICD-11	1295452752
SNOMED CT	254078005
UMLS	C0432221
MedGen	98146
GARD	0004991
Is cancer (heuristic)	no

Also known as: SMDCF · spondylometaphyseal dysplasia corner fracture type · spondylometaphyseal dysplasia Sutcliffe type · spondylometaphyseal dysplasia, Sutcliffe type · Sutcliffe SmD · Sutcliffe type of spondylometaphyseal dysplasia

Data availability: 457 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › spondylometaphyseal dysplasia › spondylometaphyseal dysplasia, ‘corner fracture’ type

Related subtypes (18): Kniest dysplasia, spondyloepimetaphyseal dysplasia, Strudwick type, spondylometaphyseal dysplasia, Kozlowski type, spondylometaphyseal dysplasia, Schmidt type, spondylometaphyseal dysplasia, Sedaghatian type, spondylometaphyseal dysplasia, Golden type, axial spondylometaphyseal dysplasia, spondylometaphyseal dysplasia-bowed forearms-facial dysmorphism syndrome, Spondyloenchondrodysplasia with immune dysregulation, spondylometaphyseal dysplasia-cone-rod dystrophy syndrome, spondylometaphyseal dysplasia, A4 type, spondylometaphyseal dysplasia, East African type, autosomal recessive spondylometaphyseal dysplasia, Megarbane type, spondylometaphyseal dysplasia, Czarny-Ratajczak type, regressive spondylometaphyseal dysplasia, spondylometaphyseal dysplasia, pagnamenta type, odontochondrodysplasia, SBDS-related severe neonatal spondylometaphyseal dysplasia

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

457 retrieved; paginated sample, class counts are floors:

258 uncertain significance, 76 conflicting classifications of pathogenicity, 44 likely benign, 42 benign/likely benign, 18 benign, 9 likely pathogenic, 6 pathogenic, 3 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1455692	NM_001844.5(COL2A1):c.2858del (p.Pro953fs)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
265429	NM_001844.5(COL2A1):c.2833G>A (p.Gly945Ser)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
449001	NM_001844.5(COL2A1):c.905C>T (p.Ala302Val)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
929262	NM_001844.5(COL2A1):c.1034G>A (p.Gly345Asp)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
16325	NM_212482.4(FN1):c.2918A>G (p.Tyr973Cys)	FN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1683462	NM_212482.4(FN1):c.261C>G (p.Cys87Trp)	FN1	Pathogenic	criteria provided, multiple submitters, no conflicts
424644	NM_212482.4(FN1):c.367T>C (p.Cys123Arg)	FN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
424645	NM_212482.4(FN1):c.675C>G (p.Cys225Trp)	FN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
638046	NM_212482.4(FN1):c.685+1G>C	FN1	Pathogenic	criteria provided, single submitter
2412782	NM_212482.4(FN1):c.685+3A>G	FN1	Likely pathogenic	criteria provided, single submitter
3064820	NM_212482.4(FN1):c.3009_3010dup (p.Gln1004fs)	FN1	Likely pathogenic	criteria provided, single submitter
3064945	NM_212482.4(FN1):c.3010_3011insTC (p.Gln1004fs)	FN1	Likely pathogenic	criteria provided, single submitter
3391107	NM_212482.4(FN1):c.938G>T (p.Gly313Val)	FN1	Likely pathogenic	criteria provided, single submitter
3585436	NM_212482.4(FN1):c.5773T>C (p.Trp1925Arg)	FN1	Likely pathogenic	criteria provided, single submitter
3906951	NM_212482.4(FN1):c.637T>C (p.Cys213Arg)	FN1	Likely pathogenic	criteria provided, single submitter
424643	NM_212482.4(FN1):c.260G>T (p.Cys87Phe)	FN1	Likely pathogenic	criteria provided, single submitter
424646	NM_212482.4(FN1):c.718T>G (p.Tyr240Asp)	FN1	Likely pathogenic	criteria provided, single submitter
424647	NM_212482.4(FN1):c.778T>G (p.Cys260Gly)	FN1	Likely pathogenic	criteria provided, single submitter
1482572	NM_212482.4(FN1):c.7070G>A (p.Arg2357His)	ATIC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2717912	NM_212482.4(FN1):c.6878C>T (p.Thr2293Met)	ATIC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003871	NM_001844.5(COL2A1):c.1057G>A (p.Ala353Thr)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1020209	NM_001844.5(COL2A1):c.3007G>A (p.Glu1003Lys)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1386179	NM_001844.5(COL2A1):c.1757G>A (p.Arg586His)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1524681	NM_001844.5(COL2A1):c.2795G>A (p.Arg932Gln)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
938269	NM_001844.5(COL2A1):c.1855G>A (p.Glu619Lys)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1000581	NM_212482.4(FN1):c.141A>C (p.Gln47His)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007901	NM_212482.4(FN1):c.5735G>A (p.Arg1912His)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1020947	NM_212482.4(FN1):c.869G>A (p.Arg290His)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1025513	NM_212482.4(FN1):c.6506C>T (p.Pro2169Leu)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1036930	NM_212482.4(FN1):c.3491C>T (p.Ala1164Val)	FN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 21 · 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
FN1	Definitive	Autosomal dominant	spondylometaphyseal dysplasia, ‘corner fracture’ type	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FN1	Orphanet:84090	Fibronectin glomerulopathy
FN1	Orphanet:93315	Spondylometaphyseal dysplasia, ‘corner fracture’ type
COL2A1	Orphanet:137678	Spondyloepiphyseal dysplasia with metatarsal shortening
COL2A1	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL2A1	Orphanet:1856	Spondyloperipheral dysplasia-short ulna syndrome
COL2A1	Orphanet:209867	Autosomal dominant rhegmatogenous retinal detachment
COL2A1	Orphanet:2380	Legg-Calvé-Perthes disease
COL2A1	Orphanet:459051	Spondyloepiphyseal dysplasia, Stanescu type
COL2A1	Orphanet:485	Kniest dysplasia
COL2A1	Orphanet:85166	Platyspondylic dysplasia, Torrance type
COL2A1	Orphanet:85198	Dysspondyloenchondromatosis
COL2A1	Orphanet:86820	Familial avascular necrosis of femoral head
COL2A1	Orphanet:90653	Stickler syndrome type 1
COL2A1	Orphanet:93279	Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis
COL2A1	Orphanet:93296	Achondrogenesis type 2
COL2A1	Orphanet:93297	Hypochondrogenesis
COL2A1	Orphanet:93315	Spondylometaphyseal dysplasia, ‘corner fracture’ type
COL2A1	Orphanet:93316	Spondylometaphyseal dysplasia, Schmidt type
COL2A1	Orphanet:93346	Spondyloepimetaphyseal dysplasia congenita, Strudwick type
COL2A1	Orphanet:94068	Spondyloepiphyseal dysplasia congenita
ATIC	Orphanet:250977	AICA-ribosiduria

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
FN1	HGNC:3778	ENSG00000115414	P02751	Fibronectin	gencc,clinvar
COL2A1	HGNC:2200	ENSG00000139219	P02458	Collagen alpha-1(II) chain	clinvar
FN1-DT	HGNC:55775	ENSG00000230695		FN1 divergent transcript	clinvar
ATIC	HGNC:794	ENSG00000138363	P31939	Bifunctional purine biosynthesis protein ATIC	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FN1	Fibronectin	Fibronectins bind cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin.
COL2A1	Collagen alpha-1(II) chain	Type II collagen is specific for cartilaginous tissues.
ATIC	Bifunctional purine biosynthesis protein ATIC	Bifunctional enzyme that catalyzes the last two steps of purine biosynthesis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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
Antibody/Immunoglobulin	1	7.3×	0.390
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FN1	Antibody/Immunoglobulin	yes		Fibronectin_type1, FN_type2_dom, FN3_dom
COL2A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
FN1-DT	Other/Unknown	no
ATIC	Enzyme (other)	yes	2.1.2.3	PurH-like, MGS-like_dom, Cytidine_deaminase-like

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
decidua	1
right coronary artery	1
synovial joint	1
cartilage tissue	1
corpus epididymis	1
tibia	1
calcaneal tendon	1
myometrium	1
sural nerve	1
mucosa of transverse colon	1
rectum	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FN1	292	ubiquitous	marker	synovial joint, right coronary artery, decidua
COL2A1	145	broad	marker	tibia, cartilage tissue, corpus epididymis
FN1-DT	96		yes	sural nerve, calcaneal tendon, myometrium
ATIC	290	ubiquitous	marker	mucosa of transverse colon, stromal cell of endometrium, rectum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FN1	8,860
ATIC	3,960
COL2A1	2,491
FN1-DT	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FN1	P02751	65
COL2A1	P02458	11
ATIC	P31939	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 37. 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
Fibronectin matrix formation	2	380.7×	3e-04	FN1, COL2A1
MET activates PTK2 signaling	2	253.8×	4e-04	FN1, COL2A1
Developmental Lineage of Pancreatic Ductal Cells	2	152.3×	7e-04	FN1, COL2A1
Non-integrin membrane-ECM interactions	2	102.9×	8e-04	FN1, COL2A1
ECM proteoglycans	2	100.2×	8e-04	FN1, COL2A1
Signaling by ALK fusions and activated point mutants	2	100.2×	8e-04	FN1, ATIC
Integrin cell surface interactions	2	89.6×	9e-04	FN1, COL2A1
Purine ribonucleoside monophosphate biosynthesis	1	346.1×	0.013	ATIC
ALK mutants bind TKIs	1	317.2×	0.013	FN1
p130Cas linkage to MAPK signaling for integrins	1	253.8×	0.014	FN1
GRB2:SOS provides linkage to MAPK signaling for Integrins	1	237.9×	0.014	FN1
Attachment of bacteria to epithelial cells	1	165.5×	0.017	FN1
Syndecan interactions	1	141.0×	0.017	FN1
Integrin signaling	1	141.0×	0.017	FN1
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	119.0×	0.017	FN1
Signaling by high-kinase activity BRAF mutants	1	105.7×	0.017	FN1
Molecules associated with elastic fibres	1	102.9×	0.017	FN1
MAP2K and MAPK activation	1	95.2×	0.017	FN1
Signaling by RAF1 mutants	1	92.8×	0.017	FN1
Collagen chain trimerization	1	86.5×	0.017	COL2A1
Signaling by PDGF	1	84.6×	0.017	COL2A1
Signaling by moderate kinase activity BRAF mutants	1	84.6×	0.017	FN1
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	84.6×	0.017	FN1
Signaling downstream of RAS mutants	1	84.6×	0.017	FN1
NCAM1 interactions	1	82.8×	0.017	COL2A1
GPER1 signaling	1	82.8×	0.017	FN1
Assembly of collagen fibrils and other multimeric structures	1	66.8×	0.020	COL2A1
Collagen degradation	1	58.6×	0.022	COL2A1
Collagen biosynthesis and modifying enzymes	1	56.8×	0.022	COL2A1
Signaling by BRAF and RAF1 fusions	1	56.8×	0.022	FN1

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
dihydrofolate metabolic process	1	1872.4×	0.006	ATIC
negative regulation of monocyte activation	1	1872.4×	0.006	FN1
calcium-independent cell-matrix adhesion	1	1404.3×	0.006	FN1
positive regulation of substrate-dependent cell migration, cell attachment to substrate	1	1404.3×	0.006	FN1
negative regulation of transforming growth factor beta production	1	1123.5×	0.006	FN1
‘de novo’ IMP biosynthetic process	1	936.2×	0.006	ATIC
cell-substrate junction assembly	1	936.2×	0.006	FN1
tetrahydrofolate biosynthetic process	1	936.2×	0.006	ATIC
biological process involved in interaction with symbiont	1	936.2×	0.006	FN1
otic vesicle development	1	936.2×	0.006	COL2A1
anterior head development	1	936.2×	0.006	COL2A1
cartilage development involved in endochondral bone morphogenesis	1	802.5×	0.006	COL2A1
brainstem development	1	702.2×	0.006	ATIC
‘de novo’ AMP biosynthetic process	1	702.2×	0.006	ATIC
‘de novo’ XMP biosynthetic process	1	702.2×	0.006	ATIC
proteoglycan metabolic process	1	624.1×	0.006	COL2A1
GMP biosynthetic process	1	624.1×	0.006	ATIC
neural crest cell migration involved in autonomic nervous system development	1	624.1×	0.006	FN1
notochord development	1	561.7×	0.006	COL2A1
blood coagulation, fibrin clot formation	1	561.7×	0.006	FN1
limb bud formation	1	510.7×	0.006	COL2A1
embryonic skeletal joint morphogenesis	1	510.7×	0.006	COL2A1
integrin activation	1	468.1×	0.006	FN1
cellular response to interleukin-7	1	432.1×	0.007	ATIC
regulation of protein phosphorylation	1	374.5×	0.007	FN1
enteric nervous system development	1	330.4×	0.008	FN1
cartilage condensation	1	255.3×	0.010	COL2A1
animal organ regeneration	1	200.6×	0.011	ATIC
response to muscle activity	1	193.7×	0.011	FN1
regulation of ERK1 and ERK2 cascade	1	193.7×	0.011	FN1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
ATIC	PEMETREXED

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATIC	3	4
FN1	0	0
COL2A1	0	0
FN1-DT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PEMETREXED	4	ATIC
METHOTREXATE	4	ATIC
SULFASALAZINE	4	ATIC

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ATIC	95	Binding:95
COL2A1	2	Binding:2
FN1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATIC	2.1.2.3, 3.5.4.10	phosphoribosylaminoimidazolecarboxamide formyltransferase, IMP cyclohydrolase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 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)
PEMETREXED	4	ATIC
METHOTREXATE	4	ATIC
SULFASALAZINE	4	ATIC

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ATIC
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	FN1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	COL2A1, FN1-DT

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FN1	1	—
COL2A1	2	—
FN1-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.