Frontometaphyseal dysplasia

Summary

Frontometaphyseal dysplasia (MONDO:0015942) is a disease caused by MAP3K7 (GenCC Strong), with 8 cohort genes and 6 clinical trials. Top therapeutic interventions include empagliflozin.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MAP3K7 (GenCC Strong)
• Cohort genes: 8
• ClinVar variants: 3,143
• Phenotypes (HPO): 62
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000336	Prominent supraorbital ridges	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000431	Wide nasal bridge	Very frequent (80-99%)
HP:0000494	Downslanted palpebral fissures	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0002652	Skeletal dysplasia	Very frequent (80-99%)
HP:0009473	Joint contracture of the hand	Very frequent (80-99%)
HP:0009803	Short phalanx of finger	Very frequent (80-99%)
HP:0011304	Broad thumb	Very frequent (80-99%)
HP:0100807	Long fingers	Very frequent (80-99%)
HP:0000126	Hydronephrosis	Frequent (30-79%)
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0000293	Full cheeks	Frequent (30-79%)
HP:0000405	Conductive hearing impairment	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000941	Short diaphyses	Frequent (30-79%)
HP:0001220	Interphalangeal joint contracture of finger	Frequent (30-79%)
HP:0001239	Wrist flexion contracture	Frequent (30-79%)
HP:0001607	Subglottic stenosis	Frequent (30-79%)
HP:0001627	Abnormal heart morphology	Frequent (30-79%)
HP:0002694	Sclerosis of skull base	Frequent (30-79%)
HP:0002949	Fused cervical vertebrae	Frequent (30-79%)
HP:0002987	Elbow flexion contracture	Frequent (30-79%)
HP:0002996	Limited elbow movement	Frequent (30-79%)
HP:0003016	Metaphyseal widening	Frequent (30-79%)
HP:0003083	Dislocated radial head	Frequent (30-79%)
HP:0006000	Ureteral obstruction	Frequent (30-79%)
HP:0006070	Metacarpophalangeal joint contracture	Frequent (30-79%)
HP:0006248	Limited wrist movement	Frequent (30-79%)
HP:0008081	Pes valgus	Frequent (30-79%)
HP:0008661	Urethral stenosis	Frequent (30-79%)
HP:0009487	Ulnar deviation of the hand	Frequent (30-79%)
HP:0009650	Short distal phalanx of the thumb	Frequent (30-79%)
HP:0009882	Short distal phalanx of finger	Frequent (30-79%)
HP:0010049	Short metacarpal	Frequent (30-79%)
HP:0010501	Limitation of knee mobility	Frequent (30-79%)
HP:0010505	Limitation of movement at ankles	Frequent (30-79%)
HP:0010562	Keloids	Frequent (30-79%)
HP:0010743	Short metatarsal	Frequent (30-79%)
HP:0100490	Camptodactyly of finger	Frequent (30-79%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000193	Bifid uvula	Occasional (5-29%)
HP:0000410	Mixed hearing impairment	Occasional (5-29%)
HP:0000481	Abnormal cornea morphology	Occasional (5-29%)
HP:0000483	Astigmatism	Occasional (5-29%)
HP:0000646	Amblyopia	Occasional (5-29%)
HP:0000677	Oligodontia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	frontometaphyseal dysplasia
Mondo ID	MONDO:0015942
MeSH	C538064
OMIM	305620
Orphanet	1826
DOID	DOID:0111785
ICD-11	1767187670
SNOMED CT	62803002
UMLS	C0265293
MedGen	82703
GARD	0000826
Is cancer (heuristic)	no

Also known as: FMD · frontometaphyseal dysplasia

Data availability: 3,143 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › filamin-related bone disorder › otopalatodigital syndrome spectrum disorder › frontometaphyseal dysplasia

Related subtypes (2): Melnick-Needles syndrome, otopalatodigital syndrome

Subtypes (2): frontometaphyseal dysplasia 2, frontometaphyseal dysplasia 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

600 retrieved; paginated sample, class counts are floors:

200 likely benign, 199 uncertain significance, 108 conflicting classifications of pathogenicity, 35 benign, 26 pathogenic, 21 benign/likely benign, 7 pathogenic/likely pathogenic, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1455467	NC_000023.10:g.(?153599231)(153609567_?)del	EMD	Pathogenic	criteria provided, single submitter
1066948	NM_001110556.2(FLNA):c.1066-1G>A	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069630	NM_001110556.2(FLNA):c.334_335insGAGAACGTGTCGG (p.Glu112fs)	FLNA	Pathogenic	criteria provided, single submitter
1070215	NM_001110556.2(FLNA):c.812del (p.Pro271fs)	FLNA	Pathogenic	criteria provided, single submitter
1070361	NM_001110556.2(FLNA):c.2947dup (p.Val983fs)	FLNA	Pathogenic	criteria provided, single submitter
1071106	NM_001110556.2(FLNA):c.6677dup (p.Gln2227fs)	FLNA	Pathogenic	criteria provided, single submitter
1071650	NM_001110556.2(FLNA):c.829_835del (p.Arg276_Pro277insTer)	FLNA	Pathogenic	criteria provided, single submitter
1072111	NM_001110556.2(FLNA):c.577C>T (p.Gln193Ter)	FLNA	Pathogenic	criteria provided, single submitter
1072754	NM_001110556.2(FLNA):c.6329_6330del (p.Glu2110fs)	FLNA	Pathogenic	criteria provided, single submitter
1073243	NM_001110556.2(FLNA):c.5146del (p.Gln1716fs)	FLNA	Pathogenic	criteria provided, single submitter
1075551	NM_001110556.2(FLNA):c.2965C>T (p.Gln989Ter)	FLNA	Pathogenic	criteria provided, single submitter
1075693	NM_001110556.2(FLNA):c.4138dup (p.Thr1380fs)	FLNA	Pathogenic	criteria provided, single submitter
11754	NM_001110556.2(FLNA):c.245A>T (p.Glu82Val)	FLNA	Pathogenic	criteria provided, single submitter
11755	NM_001110556.2(FLNA):c.620C>T (p.Pro207Leu)	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11756	NM_001110556.2(FLNA):c.760G>A (p.Glu254Lys)	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11758	NM_001110556.2(FLNA):c.3562G>A (p.Ala1188Thr)	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11759	NM_001110556.2(FLNA):c.3596C>T (p.Ser1199Leu)	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11761	NM_001110556.2(FLNA):c.3557C>T (p.Ser1186Leu)	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11775	NM_001110556.2(FLNA):c.5217G>A (p.Thr1739=)	FLNA	Pathogenic	criteria provided, multiple submitters, no conflicts
11777	NM_001110556.2(FLNA):c.862G>A (p.Gly288Arg)	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1254666	NM_001110556.2(FLNA):c.257AGA[2] (p.Lys88del)	FLNA	Pathogenic	criteria provided, multiple submitters, no conflicts
1383677	NM_001110556.2(FLNA):c.6318C>G (p.Tyr2106Ter)	FLNA	Pathogenic	criteria provided, single submitter
1399735	NM_001110556.2(FLNA):c.7285_7286dup (p.Gly2430fs)	FLNA	Pathogenic	criteria provided, single submitter
1407335	NM_001110556.2(FLNA):c.2191_2192insGT (p.Tyr731fs)	FLNA	Pathogenic	criteria provided, single submitter
1429750	NM_001110556.2(FLNA):c.1759G>T (p.Glu587Ter)	FLNA	Pathogenic	criteria provided, single submitter
1434332	NM_001110556.2(FLNA):c.2751_2752dup (p.Asp918fs)	FLNA	Pathogenic	criteria provided, single submitter
1444364	NM_001110556.2(FLNA):c.1112_1113dup (p.Val372fs)	FLNA	Pathogenic	criteria provided, single submitter
1451173	NM_001110556.2(FLNA):c.656del (p.Ser219fs)	FLNA	Pathogenic	criteria provided, single submitter
1452088	NM_001110556.2(FLNA):c.2963_2964del (p.Asp988fs)	FLNA	Pathogenic	criteria provided, single submitter
1455761	NM_001110556.2(FLNA):c.6898C>T (p.Gln2300Ter)	FLNA	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 40 · Orphanet: 20 · 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
FLNA	Definitive	X-linked	terminal osseous dysplasia-pigmentary defects syndrome	30
MAP3K7	Strong	Autosomal dominant	frontometaphyseal dysplasia 2	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FLNA	Orphanet:1826	Frontometaphyseal dysplasia
FLNA	Orphanet:2301	Congenital short bowel syndrome
FLNA	Orphanet:2484	Melnick-Needles syndrome
FLNA	Orphanet:482606	X-linked keloid scarring-reduced joint mobility-increased optic cup-to-disc ratio syndrome
FLNA	Orphanet:555877	FLNA-related X-linked myxomatous valvular dysplasia
FLNA	Orphanet:75497	X-linked Ehlers-Danlos syndrome
FLNA	Orphanet:88630	Terminal osseous dysplasia-pigmentary defects syndrome
FLNA	Orphanet:90650	Otopalatodigital syndrome type 1
FLNA	Orphanet:90652	Otopalatodigital syndrome type 2
FLNA	Orphanet:98892	Periventricular nodular heterotopia
FLNA	Orphanet:99811	Neuronal intestinal pseudoobstruction
MAP3K7	Orphanet:1826	Frontometaphyseal dysplasia
MAP3K7	Orphanet:3238	Cardiospondylocarpofacial syndrome
EMD	Orphanet:98863	X-linked Emery-Dreifuss muscular dystrophy
HCFC1	Orphanet:369962	Methylmalonic acidemia with homocystinuria, type cblX
HCFC1	Orphanet:777	X-linked non-syndromic intellectual disability
ABCD1	Orphanet:139396	X-linked cerebral adrenoleukodystrophy
ABCD1	Orphanet:139399	Adrenomyeloneuropathy
ABCD1	Orphanet:369942	CADDS
ABCD1	Orphanet:388	Hirschsprung disease

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FLNA	HGNC:3754	ENSG00000196924	P21333	Filamin-A	gencc,clinvar
MAP3K7	HGNC:6859	ENSG00000135341	O43318	Mitogen-activated protein kinase kinase kinase 7	gencc
OPN1MW2	HGNC:26952	ENSG00000166160	P0DN77	Medium-wave-sensitive opsin 2	clinvar
DNASE1L1	HGNC:2957	ENSG00000013563	P49184	Deoxyribonuclease-1-like 1	clinvar
EMD	HGNC:3331	ENSG00000102119	P50402	Emerin	clinvar
HCFC1	HGNC:4839	ENSG00000172534	P51610	Host cell factor 1	clinvar
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	clinvar
ARHGAP4	HGNC:674	ENSG00000089820	P98171	Rho GTPase-activating protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FLNA	Filamin-A	Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins.
MAP3K7	Mitogen-activated protein kinase kinase kinase 7	Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway.
OPN1MW2	Medium-wave-sensitive opsin 2	Visual pigments are the light-absorbing molecules that mediate vision.
EMD	Emerin	Stabilizes and promotes the formation of a nuclear actin cortical network.
HCFC1	Host cell factor 1	Transcriptional coregulator.
ABCD1	ATP-binding cassette sub-family D member 1	ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen.
ARHGAP4	Rho GTPase-activating protein 4	Inhibitory effect on stress fiber organization.

Protein-family classification

Druggable: 6 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.75

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	2	7.3×	0.200
Phosphatase	1	10.5×	0.229
Transporter	1	9.7×	0.229
Kinase	1	3.5×	0.405
GPCR	1	3.0×	0.405
Scaffold/PPI	1	2.2×	0.442
Other/Unknown	1	0.2×	0.999

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLNA	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
MAP3K7	Kinase	yes		Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ser/Thr_kinase_AS
OPN1MW2	GPCR	yes		GPCR_Rhodpsn, Opsin_red/grn, Opsin
DNASE1L1	Phosphatase	yes		Endo/exonuclease/phosphatase, DNase_I, Deoxyribonuclease-1_AS
EMD	Other/Unknown	no		LEM_dom, LEM/LEM-like_dom_sf, LEM_emerin
HCFC1	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, Kelch-typ_b-propeller
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter
ARHGAP4	Scaffold/PPI	no		RhoGAP_dom, FCH_dom, SH3_domain

Expression context

Cohort genes with no expression data: 0.

7 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	1
moderate (6-20)	0
broad (>20)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
popliteal artery	2
tendon of biceps brachii	2
right coronary artery	1
tibial artery	1
corpus epididymis	1
tendon	1
colonic epithelium	1
primordial germ cell in gonad	1
ventricular zone	1
gastrocnemius	1
gluteal muscle	1
hindlimb stylopod muscle	1
left ovary	1
left uterine tube	1
parotid gland	1
skeletal muscle tissue of rectus abdominis	1
ileal mucosa	1
left adrenal gland	1
left adrenal gland cortex	1
granulocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FLNA	285	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
MAP3K7	290	ubiquitous	marker	tendon of biceps brachii, tendon, corpus epididymis
OPN1MW2	4		yes	primordial germ cell in gonad, colonic epithelium, ventricular zone
DNASE1L1	283	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, gluteal muscle
EMD	284	ubiquitous	marker	left ovary, left uterine tube, popliteal artery
HCFC1	274	ubiquitous	marker	tendon of biceps brachii, parotid gland, skeletal muscle tissue of rectus abdominis
ABCD1	201	ubiquitous	marker	ileal mucosa, left adrenal gland cortex, left adrenal gland
ARHGAP4	229	broad	marker	granulocyte, spleen, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAP3K7	5,457
FLNA	5,321
EMD	3,503
HCFC1	2,637
ABCD1	1,181
ARHGAP4	1,088
DNASE1L1	1,012
OPN1MW2	346

Structural data

PDB: 6 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FLNA	P21333	26
MAP3K7	O43318	25
ABCD1	P33897	14
HCFC1	P51610	11
EMD	P50402	6
ARHGAP4	P98171	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNASE1L1	P49184	90.83
OPN1MW2	P0DN77	82.82

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 99. Enrichment computed across 8 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCD1 causes ALD	1	815.7×	0.058	ABCD1
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	271.9×	0.058	ABCD1
OAS antiviral response	1	181.3×	0.058	FLNA
Linoleic acid (LA) metabolism	1	163.1×	0.058	ABCD1
IRAK2 mediated activation of TAK1 complex	1	163.1×	0.058	MAP3K7
TICAM1,TRAF6-dependent induction of TAK1 complex	1	148.3×	0.058	MAP3K7
Alpha-protein kinase 1 signaling pathway	1	148.3×	0.058	MAP3K7
GP1b-IX-V activation signalling	1	135.9×	0.058	FLNA
Beta-oxidation of very long chain fatty acids	1	125.5×	0.058	ABCD1
Downstream signaling events of B Cell Receptor (BCR)	1	116.5×	0.058	MAP3K7
Depolymerization of the Nuclear Lamina	1	108.8×	0.058	EMD
IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation	1	108.8×	0.058	MAP3K7
alpha-linolenic acid (ALA) metabolism	1	102.0×	0.058	ABCD1
TRAF6-mediated induction of TAK1 complex within TLR4 complex	1	102.0×	0.058	MAP3K7
Peroxisomal lipid metabolism	1	96.0×	0.058	ABCD1
Cell-extracellular matrix interactions	1	96.0×	0.058	FLNA
ABC transporters in lipid homeostasis	1	85.9×	0.058	ABCD1
Initiation of Nuclear Envelope (NE) Reformation	1	85.9×	0.058	EMD
RHO GTPases activate PAKs	1	77.7×	0.058	FLNA
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	1	74.2×	0.058	MAP3K7
Class I peroxisomal membrane protein import	1	74.2×	0.058	ABCD1
TCR signaling	1	70.9×	0.058	MAP3K7
activated TAK1 mediates p38 MAPK activation	1	70.9×	0.058	MAP3K7
RAC1 GTPase cycle	2	17.4×	0.058	EMD, ARHGAP4
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	1	68.0×	0.058	EMD
Nuclear Envelope Breakdown	1	65.3×	0.058	EMD
ABC transporter disorders	1	62.8×	0.058	ABCD1
TNF signaling	1	60.4×	0.058	MAP3K7
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1	51.0×	0.066	MAP3K7
Signaling by the B Cell Receptor (BCR)	1	49.4×	0.066	MAP3K7

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of membrane repolarization during atrial cardiac muscle cell action potential	1	2106.5×	0.017	FLNA
regulation of membrane repolarization during cardiac muscle cell action potential	1	2106.5×	0.017	FLNA
peroxisomal membrane transport	1	1053.2×	0.017	ABCD1
very long-chain fatty-acyl-CoA catabolic process	1	1053.2×	0.017	ABCD1
I-kappaB phosphorylation	1	702.2×	0.017	MAP3K7
release from viral latency	1	702.2×	0.017	HCFC1
tubulin deacetylation	1	702.2×	0.017	FLNA
positive regulation of unsaturated fatty acid biosynthetic process	1	702.2×	0.017	ABCD1
formation of radial glial scaffolds	1	526.6×	0.017	FLNA
sterol homeostasis	1	526.6×	0.017	ABCD1
adenylate cyclase-inhibiting dopamine receptor signaling pathway	1	421.3×	0.017	FLNA
long-chain fatty acid import into peroxisome	1	421.3×	0.017	ABCD1
establishment of Sertoli cell barrier	1	421.3×	0.017	FLNA
absorption of visible light	1	351.1×	0.017	OPN1MW2
regulation of fatty acid beta-oxidation	1	351.1×	0.017	ABCD1
nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	1	351.1×	0.017	MAP3K7
interleukin-17A-mediated signaling pathway	1	351.1×	0.017	MAP3K7
long-chain fatty acid catabolic process	1	351.1×	0.017	ABCD1
myelin maintenance	1	351.1×	0.017	ABCD1
regulation of mitochondrial depolarization	1	351.1×	0.017	ABCD1
protein localization to bicellular tight junction	1	351.1×	0.017	FLNA
negative regulation of transcription by RNA polymerase I	1	300.9×	0.017	FLNA
fatty acid elongation	1	300.9×	0.017	ABCD1
very long-chain fatty acid catabolic process	1	300.9×	0.017	ABCD1
nuclear membrane organization	1	300.9×	0.017	EMD
positive regulation of cell cycle	2	110.9×	0.017	HCFC1, MAP3K7
blood coagulation, intrinsic pathway	1	263.3×	0.018	FLNA
interleukin-33-mediated signaling pathway	1	263.3×	0.018	MAP3K7
positive regulation of cGAS/STING signaling pathway	1	263.3×	0.018	MAP3K7
negative regulation of fibroblast migration	1	191.5×	0.020	ARHGAP4

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 3 · Undrugged: 5

Druggability breadth: 4 of 8 evidence-associated genes (50%) 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
MAP3K7	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP3K7	29	4
FLNA	1	2
HCFC1	1	2
OPN1MW2	0	0
DNASE1L1	0	0
EMD	0	0
ABCD1	0	0
ARHGAP4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	MAP3K7
SORAFENIB	4	MAP3K7
RUXOLITINIB	4	MAP3K7
BOSUTINIB	4	MAP3K7
ADENOSINE	4	MAP3K7
NINTEDANIB	4	MAP3K7
SUNITINIB	4	MAP3K7
DASATINIB	4	MAP3K7
QUIZARTINIB	4	MAP3K7
CRIZOTINIB	4	MAP3K7
MIDOSTAURIN	4	MAP3K7
CANERTINIB	3	MAP3K7
ALVOCIDIB	3	MAP3K7
DOVITINIB	3	MAP3K7
MOTESANIB	3	MAP3K7
LESTAURTINIB	3	MAP3K7
MOLIBRESIB	2	FLNA, HCFC1
DORAMAPIMOD	2	MAP3K7
FORETINIB	2	MAP3K7
ADENOSINE TRIPHOSPHATE	2	MAP3K7
SU-014813	2	MAP3K7
REBASTINIB	2	MAP3K7
DEFOSBARASERTIB	2	MAP3K7
TG100-115	2	MAP3K7
R-406	2	MAP3K7
RAF-265	2	MAP3K7
TOZASERTIB	2	MAP3K7
KW-2449	1	MAP3K7
BMS-387032	1	MAP3K7
AST-487	1	MAP3K7

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MAP3K7	375	Binding:374, ADMET:1
HCFC1	8	Binding:8
FLNA	7	Binding:7
EMD	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCD1	7.6.2.4	ABC-type fatty-acyl-CoA transporter

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MAP3K7	375

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; 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)
FEDRATINIB	4	MAP3K7
SORAFENIB	4	MAP3K7
RUXOLITINIB	4	MAP3K7
BOSUTINIB	4	MAP3K7
ADENOSINE	4	MAP3K7
NINTEDANIB	4	MAP3K7
SUNITINIB	4	MAP3K7
DASATINIB	4	MAP3K7
QUIZARTINIB	4	MAP3K7
CRIZOTINIB	4	MAP3K7
MIDOSTAURIN	4	MAP3K7
CANERTINIB	3	MAP3K7
ALVOCIDIB	3	MAP3K7
DOVITINIB	3	MAP3K7
MOTESANIB	3	MAP3K7
LESTAURTINIB	3	MAP3K7
MOLIBRESIB	2	FLNA, HCFC1
DORAMAPIMOD	2	MAP3K7
FORETINIB	2	MAP3K7
ADENOSINE TRIPHOSPHATE	2	MAP3K7
SU-014813	2	MAP3K7
REBASTINIB	2	MAP3K7
DEFOSBARASERTIB	2	MAP3K7
TG100-115	2	MAP3K7
R-406	2	MAP3K7
RAF-265	2	MAP3K7
TOZASERTIB	2	MAP3K7
KW-2449	1	MAP3K7
BMS-387032	1	MAP3K7
AST-487	1	MAP3K7

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MAP3K7
B	Phased (≥1) drug, not yet approved	2	FLNA, HCFC1
C	Druggable family + PDB, no drug	1	ABCD1
D	Druggable family + AlphaFold only, no drug	2	OPN1MW2, DNASE1L1
E	Difficult family or no structure, no drug	2	EMD, ARHGAP4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
OPN1MW2	0	—
DNASE1L1	0	—
EMD	1	—
ABCD1	0	—
ARHGAP4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE4	1
PHASE1/PHASE2	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05857085	PHASE4	COMPLETED	Novel Therapeutics and Endothelial Dysfunction in T1DM Patients
NCT06547216	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Open-label Extension Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT05747924	PHASE1/PHASE2	COMPLETED	Phase 1/2 Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT01862146	Not specified	COMPLETED	Arterial Remodeling in Smokers
NCT02127333	Not specified	COMPLETED	Role of Oxygen for Vascular Dysfunction
NCT04199949	Not specified	COMPLETED	Effects of Five Days of Physical Inactivity on Endothelial Function in Healthy Humans

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EMPAGLIFLOZIN	4	1
CHEMBL5177502	0	1