Flatfoot

Summary

Flatfoot (MONDO:0005293) is a disease with 13 cohort genes (3 GWAS associations across 8 studies) and 39 clinical trials. Top therapeutic interventions include chloroprocaine, sodium chloride, and durapatite.

At a glance

• Cohort genes: 13
• GWAS associations: 3
• ClinVar variants: 19
• Clinical trials: 39

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	flatfoot
Mondo ID	MONDO:0005293
EFO	EFO:0003874
MeSH	D005413
NCIT	C34616
SNOMED CT	53226007
UMLS	C0016202
MedGen	42034
Is cancer (heuristic)	no

Also known as: fallen Arch · flat Foot

Data availability: 19 ClinVar variants · 3 GWAS associations (8 studies).

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › flatfoot

Related subtypes (47): symphalangism, cartilage cancer, vertebral column disorder, patellar tendinitis, necrosis of ear ossicle, laryngeal cartilage cancer, ochronosis disorder, chondroma, periodontal disorder, posterior cranial fossa meningioma, anterior cranial fossa meningioma, middle cranial fossa meningioma, bone marrow disorder, cranial nodular fasciitis, bone disorder, skeletal tuberculosis, arthropathy, tooth disorder, primary basilar invagination, Brachymorphism-onychodysplasia-dysphalangism syndrome, cherubism, fibrodysplasia ossificans progressiva, Marfan syndrome, Buschke-Ollendorff syndrome, scalp defects-postaxial polydactyly syndrome, cartilage-hair hypoplasia, Teebi-Shaltout syndrome, short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome, ossification of the posterior longitudinal ligament of the spine, temtamy preaxial brachydactyly syndrome, metaphyseal undermodeling, spondylar dysplasia, and overgrowth, Al-Gazali syndrome, brachydactyly-syndactyly syndrome, endocrine-cerebro-osteodysplasia syndrome, metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, multiple congenital anomalies-hypotonia-seizures syndrome 3, Rienhoff syndrome, Coffin-Siris syndrome, microcephaly-brachydactyly-kyphoscoliosis syndrome, cartilage development disorder, syndactyly, polydactyly, brachydactyly, sternal neoplasm, short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis, skeletal ligament disorder, brachydactyly-syndactyly-oligodactyly syndrome

Genetics & variants

GWAS landscape

3 GWAS associations across 8 studies. Top hits map to 1 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs725908	6e-15	UQCC1	T	0.08
chr10:73948817	1e-08		?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90476248	Verma A	2024	14,044	424,302	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90478981	Verma A	2024	10,672	103,382	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480532	Verma A	2024	10,672	103,382	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90478980	Verma A	2024	2,320	55,296	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90482420	Verma A	2024	300	6,269	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90436707	Zhou W	2018	193	394,914	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90651485	Liu TY	2025	108	227,954	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90044577	Jiang L	2021	102	456,246	A generalized linear mixed model association tool for biobank-scale data.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	2

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intron_variant	1
unknown	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs725908	20	35380264	T>C	0.474	intron_variant	UQCC1	6e-15	Tier 4: intronic/intergenic
chr10:73948817							1e-08	Tier 4: intronic/intergenic

ClinVar germline variants

19 retrieved; paginated sample, class counts are floors:

9 pathogenic, 5 conflicting classifications of pathogenicity, 2 uncertain significance, 2 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
267902	46;XY;t(3;5)(q24;p15.3)dn		Pathogenic	criteria provided, single submitter
268006	46;XY;t(6;11)(p12.3;p14.2)dn		Pathogenic	criteria provided, single submitter
374094	NM_004208.4(AIFM1):c.1019T>C (p.Met340Thr)	AIFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523274	GRCh37/hg19 22q11.21(chr22:18894835-21505417)	ARVCF	Pathogenic	criteria provided, single submitter
523528	NM_020549.5(CHAT):c.1061C>T (p.Thr354Met)	CHAT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523529	NM_020549.5(CHAT):c.2081C>G (p.Ser694Cys)	CHAT	Pathogenic	criteria provided, multiple submitters, no conflicts
373981	NM_000138.5(FBN1):c.6800A>T (p.Asn2267Ile)	FBN1	Pathogenic	no assertion criteria provided
978559	NM_000138.5(FBN1):c.3757_3760del (p.Gln1253fs)	FBN1	Pathogenic	criteria provided, single submitter
804287	NM_002109.6(HARS1):c.910_912dup (p.Leu305dup)	HARS1	Pathogenic	criteria provided, single submitter
523416	NM_001145026.2(PTPRQ):c.6475C>T (p.Arg2159Ter)	PTPRQ	Pathogenic	criteria provided, multiple submitters, no conflicts
1804057	NM_003601.4(SMARCA5):c.2677G>A (p.Glu893Lys)	SMARCA5	Pathogenic	criteria provided, multiple submitters, no conflicts
2430245	NM_002235.5(KCNA6):c.1367T>A (p.Val456Asp)	KCNA6	Likely pathogenic	criteria provided, single submitter
460433	NM_000098.3(CPT2):c.236A>C (p.Lys79Thr)	CPT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
523331	NM_000098.3(CPT2):c.1436A>T (p.Tyr479Phe)	CPT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
568701	NM_000138.5(FBN1):c.1900T>C (p.Ser634Pro)	FBN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
804288	NM_002109.6(HARS1):c.1393A>C (p.Ile465Leu)	HARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
932283	NM_000214.3(JAG1):c.3506G>A (p.Arg1169Gln)	JAG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
523498	NM_012310.5(KIF4A):c.1553G>C (p.Arg518Pro)	KIF4A	Uncertain significance	criteria provided, single submitter
2571641	NM_005428.4(VAV1):c.909del (p.Asp303fs)	VAV1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 29 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMARCA5	Orphanet:370334	Extraskeletal Ewing sarcoma
CHAT	Orphanet:98914	Presynaptic congenital myasthenic syndromes
CPT2	Orphanet:228302	Carnitine palmitoyl transferase II deficiency, myopathic form
CPT2	Orphanet:228305	Carnitine palmitoyl transferase II deficiency, severe infantile form
CPT2	Orphanet:228308	Carnitine palmitoyl transferase II deficiency, neonatal form
CPT2	Orphanet:263524	Acute necrotizing encephalopathy of childhood
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
HARS1	Orphanet:231183	Usher syndrome type 3
HARS1	Orphanet:488333	Autosomal dominant Charcot-Marie-Tooth disease type 2W
JAG1	Orphanet:261600	Alagille syndrome due to 20p12 microdeletion
JAG1	Orphanet:261619	Alagille syndrome due to a JAG1 point mutation
JAG1	Orphanet:3303	Tetralogy of Fallot
ARVCF	Orphanet:567	22q11.2 deletion syndrome
AIFM1	Orphanet:101078	X-linked Charcot-Marie-Tooth disease type 4
AIFM1	Orphanet:139583	X-linked hereditary sensory and autonomic neuropathy with deafness
AIFM1	Orphanet:238329	Severe X-linked mitochondrial encephalomyopathy
AIFM1	Orphanet:83629	Leukoencephalopathy-spondyloepimetaphyseal dysplasia syndrome
PTPRQ	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
PTPRQ	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

Cohort genes → proteins

13 cohort genes, 13 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	13

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMARCA5	HGNC:11101	ENSG00000153147	O60264	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5	clinvar
VAV1	HGNC:12657	ENSG00000141968	P15498	Proto-oncogene vav	clinvar
KIF4A	HGNC:13339	ENSG00000090889	O95239	Chromosome-associated kinesin KIF4A	clinvar
CHAT	HGNC:1912	ENSG00000070748	P28329	Choline O-acetyltransferase	clinvar
CPT2	HGNC:2330	ENSG00000157184	P23786	Carnitine O-palmitoyltransferase 2, mitochondrial	clinvar
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	clinvar
HARS1	HGNC:4816	ENSG00000170445	P12081	Histidine–tRNA ligase, cytoplasmic	clinvar
JAG1	HGNC:6188	ENSG00000101384	P78504	Protein jagged-1	clinvar
KCNA6	HGNC:6225	ENSG00000151079	P17658	Potassium voltage-gated channel subfamily A member 6	clinvar
ARVCF	HGNC:728	ENSG00000099889	O00192	Splicing regulator ARVCF	clinvar
AIFM1	HGNC:8768	ENSG00000156709	O95831	Apoptosis-inducing factor 1, mitochondrial	clinvar
PTPRQ	HGNC:9679	ENSG00000139304	Q9UMZ3	Phosphatidylinositol phosphatase PTPRQ	clinvar
PTPRR	HGNC:9680	ENSG00000153233	Q15256	Receptor-type tyrosine-protein phosphatase R	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMARCA5	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5	ATPase that possesses intrinsic ATP-dependent nucleosome-remodeling activity.
VAV1	Proto-oncogene vav	Couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, thus leading to cell differentiation and/or proliferation.
KIF4A	Chromosome-associated kinesin KIF4A	Iron-sulfur (Fe-S) cluster binding motor protein that has a role in chromosome segregation during mitosis.
CHAT	Choline O-acetyltransferase	Catalyzes the reversible synthesis of acetylcholine (ACh) from acetyl CoA and choline at cholinergic synapses.
CPT2	Carnitine O-palmitoyltransferase 2, mitochondrial	Involved in the intramitochondrial synthesis of acylcarnitines from accumulated acyl-CoA metabolites.
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.
HARS1	Histidine–tRNA ligase, cytoplasmic	Catalyzes the ATP-dependent ligation of histidine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP).
JAG1	Protein jagged-1	Ligand for multiple Notch receptors and involved in the mediation of Notch signaling.
KCNA6	Potassium voltage-gated channel subfamily A member 6	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes.
ARVCF	Splicing regulator ARVCF	Contributes to the regulation of alternative splicing of pre-mRNAs.
AIFM1	Apoptosis-inducing factor 1, mitochondrial	Functions both as NADH oxidoreductase and as regulator of apoptosis.
PTPRQ	Phosphatidylinositol phosphatase PTPRQ	Dephosphorylates phosphatidylinositol phosphates, such as phosphatidylinositol 3,4,5-trisphosphate (PIP3) and phosphatidylinositol 3,5-diphosphates, with preference for PIP3.
PTPRR	Receptor-type tyrosine-protein phosphatase R	Sequesters mitogen-activated protein kinases (MAPKs) such as MAPK1, MAPK3 and MAPK14 in the cytoplasm in an inactive form.

Protein-family classification

Druggable: 7 · Difficult: 2 · Unknown: 4 · Druggable fraction: 0.54

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
Phosphatase	2	12.9×	0.056
Enzyme (other)	4	3.7×	0.056
Ion channel	1	8.6×	0.221
Scaffold/PPI	1	1.3×	0.809
Transcription factor	1	0.6×	0.976
Other/Unknown	4	0.6×	0.982

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMARCA5	Transcription factor	no		SNF2_N, SANT/Myb, Helicase_C-like
VAV1	Scaffold/PPI	no		DH_dom, SH2, GDS_CDC24_CS
KIF4A	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
CHAT	Enzyme (other)	yes	2.3.1.6	Carn_acyl_trans, CAT-like_dom_sf, Cho/carn_acyl_trans_1_2
CPT2	Enzyme (other)	yes	2.3.1.21	Carn_acyl_trans, CAT-like_dom_sf, Cho/carn_acyl_trans_1_2
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
HARS1	Enzyme (other)	yes	6.1.1.21	WHEP-TRS_dom, Anticodon-bd, HisRS/HisZ
JAG1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, VWF_dom
KCNA6	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
ARVCF	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold
AIFM1	Enzyme (other)	yes	7.1.1.2	FAD/NAD-linked_Rdtase_dimer_sf, FAD/NAD-binding_dom, AIF_C
PTPRQ	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat
PTPRR	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat

Expression context

Cohort genes with no expression data: 0.

11 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)	13
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	2
male germ line stem cell (sensu Vertebrata) in testis	2
skin of hip	2
cerebellar cortex	2
right hemisphere of cerebellum	2
buccal mucosa cell	1
calcaneal tendon	1
granulocyte	1
leukocyte	1
monocyte	1
oocyte	1
secondary oocyte	1
primordial germ cell in gonad	1
putamen	1
jejunal mucosa	1
mucosa of transverse colon	1
right lobe of liver	1
decidua	1
synovial joint	1
adenohypophysis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMARCA5	300	ubiquitous	marker	ventricular zone, calcaneal tendon, buccal mucosa cell
VAV1	188	broad	marker	granulocyte, monocyte, leukocyte
KIF4A	179	broad	marker	oocyte, secondary oocyte, ventricular zone
CHAT	68	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, putamen
CPT2	254	ubiquitous	marker	mucosa of transverse colon, jejunal mucosa, right lobe of liver
FBN1	275	ubiquitous	marker	synovial joint, skin of hip, decidua
HARS1	291	ubiquitous	marker	lateral nuclear group of thalamus, right frontal lobe, adenohypophysis
JAG1	297	ubiquitous	marker	upper leg skin, skin of hip, blood vessel layer
KCNA6	123	tissue_specific	yes	cortical plate, male germ line stem cell (sensu Vertebrata) in testis, prefrontal cortex
ARVCF	273	ubiquitous	yes	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
AIFM1	273	ubiquitous	marker	apex of heart, adult mammalian kidney, heart left ventricle
PTPRQ	119	tissue_specific	marker	thyroid gland, left lobe of thyroid gland, right lung
PTPRR	184	tissue_specific	marker	endothelial cell, right hemisphere of cerebellum, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMARCA5	6,214
AIFM1	4,780
JAG1	4,405
FBN1	3,640
VAV1	3,042
HARS1	2,480
CPT2	2,303
KIF4A	1,982
CHAT	1,743
PTPRR	1,437

Structural data

PDB: 10 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AIFM1	O95831	26
SMARCA5	O60264	15
FBN1	P35555	11
VAV1	P15498	10
HARS1	P12081	10
CHAT	P28329	8
JAG1	P78504	7
KIF4A	O95239	1
PTPRQ	Q9UMZ3	1
PTPRR	Q15256	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CPT2	P23786	94.52
KCNA6	P17658	75.42
ARVCF	O00192	65.73

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 100. Enrichment computed across 13 evidence-associated genes (9 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 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	317.2×	0.074	JAG1
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	181.3×	0.074	JAG1
Signaling by NOTCH1 HD Domain Mutants in Cancer	1	141.0×	0.074	JAG1
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	115.3×	0.074	JAG1
CD28 dependent Vav1 pathway	1	97.6×	0.074	VAV1
Nephron development	1	97.6×	0.074	JAG1
RUNX3 regulates NOTCH signaling	1	90.6×	0.074	JAG1
Kidney development	1	90.6×	0.074	JAG1
Carnitine shuttle	1	84.6×	0.074	CPT2
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	84.6×	0.074	JAG1
Erythropoietin activates RAS	1	84.6×	0.074	VAV1
Signaling by NOTCH2	1	79.3×	0.074	JAG1
Acetylcholine Neurotransmitter Release Cycle	1	74.6×	0.074	CHAT
Signaling by NOTCH3	1	57.7×	0.074	JAG1
Signaling by NOTCH4	1	55.2×	0.074	JAG1
Regulation of signaling by CBL	1	55.2×	0.074	VAV1
Azathioprine ADME	1	55.2×	0.074	VAV1
DNA Double Strand Break Response	1	52.9×	0.074	SMARCA5
Nucleosome assembly	1	52.9×	0.074	SMARCA5
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	52.9×	0.074	JAG1
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	48.8×	0.074	JAG1
Cytosolic tRNA aminoacylation	1	48.8×	0.074	HARS1
Synthesis of PC	1	45.3×	0.074	CHAT
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	45.3×	0.074	JAG1
Signaling by NOTCH1 in Cancer	1	45.3×	0.074	JAG1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	45.3×	0.074	JAG1
VEGFR2 mediated vascular permeability	1	45.3×	0.074	VAV1
Signaling by NOTCH1	1	39.6×	0.074	JAG1
Activated NOTCH1 Transmits Signal to the Nucleus	1	39.6×	0.074	JAG1
FCERI mediated Ca+2 mobilization	1	39.6×	0.074	VAV1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
endocardial cushion cell development	1	1296.3×	0.027	JAG1
histidyl-tRNA aminoacylation	1	648.1×	0.027	HARS1
loop of Henle development	1	648.1×	0.027	JAG1
negative regulation of mitotic chromosome condensation	1	648.1×	0.027	SMARCA5
acetylcholine biosynthetic process	1	432.1×	0.027	CHAT
protein import into mitochondrial intermembrane space	1	432.1×	0.027	AIFM1
post-embryonic eye morphogenesis	1	432.1×	0.027	FBN1
spindle elongation	1	432.1×	0.027	KIF4A
cardiac neural crest cell development involved in outflow tract morphogenesis	1	432.1×	0.027	JAG1
distal tubule development	1	432.1×	0.027	JAG1
protein import into the intermembrane space via the disulfide relay system	1	432.1×	0.027	AIFM1
inhibition of neuroepithelial cell differentiation	1	324.1×	0.027	JAG1
carnitine shuttle	1	324.1×	0.027	CPT2
obsolete sequestering of BMP in extracellular matrix	1	324.1×	0.027	FBN1
obsolete sequestering of TGFbeta in extracellular matrix	1	324.1×	0.027	FBN1
ciliary body morphogenesis	1	324.1×	0.027	JAG1
positive regulation of cardiac epithelial to mesenchymal transition	1	324.1×	0.027	JAG1
organelle organization	1	259.3×	0.028	KIF4A
negative regulation of endothelial cell differentiation	1	259.3×	0.028	JAG1
positive regulation of myeloid cell differentiation	1	259.3×	0.028	JAG1
negative regulation of osteoclast development	1	259.3×	0.028	FBN1
mitochondrial respiratory chain complex assembly	1	216.1×	0.028	AIFM1
positive regulation of necroptotic process	1	216.1×	0.028	AIFM1
pulmonary artery morphogenesis	1	216.1×	0.028	JAG1
rDNA heterochromatin formation	1	185.2×	0.028	SMARCA5
carnitine metabolic process	1	185.2×	0.028	CPT2
negative regulation of transcription by RNA polymerase I	1	185.2×	0.028	SMARCA5
neuroendocrine cell differentiation	1	185.2×	0.028	JAG1
cellular response to aldosterone	1	185.2×	0.028	AIFM1
immune response-regulating cell surface receptor signaling pathway	1	144.0×	0.033	VAV1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 11

Druggability breadth: 10 of 13 evidence-associated genes (77%) 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
CPT2	PERHEXILINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CPT2	2	4
CHAT	1	3
SMARCA5	0	0
VAV1	0	0
KIF4A	0	0
FBN1	0	0
HARS1	0	0
JAG1	0	0
KCNA6	0	0
ARVCF	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PERHEXILINE	4	CPT2
COENZYME_A	3	CHAT
TEGLICAR	2	CPT2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 6.

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

Symbol	Assays	Type breakdown
KCNA6	29	Binding:24, Functional:3, Toxicity:1, ADMET:1
KIF4A	20	Binding:20
CPT2	12	Binding:12
CHAT	7	Binding:7
HARS1	5	Binding:5
PTPRR	3	Binding:3
AIFM1	2	Binding:2
SMARCA5	1	Binding:1
VAV1	1	Binding:1
JAG1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CHAT	2.3.1.6	choline O-acetyltransferase
CPT2	2.3.1.21	carnitine O-palmitoyltransferase
HARS1	6.1.1.21	histidine-tRNA ligase
AIFM1	7.1.1.2	NADH:ubiquinone reductase (H+-translocating)
PTPRQ	3.1.3.48	protein-tyrosine-phosphatase
PTPRR	3.1.3.48	protein-tyrosine-phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; 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)
PERHEXILINE	4	CPT2
COENZYME_A	3	CHAT
TEGLICAR	2	CPT2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CPT2
B	Phased (≥1) drug, not yet approved	1	CHAT
C	Druggable family + PDB, no drug	4	HARS1, AIFM1, PTPRQ, PTPRR
D	Druggable family + AlphaFold only, no drug	1	KCNA6
E	Difficult family or no structure, no drug	6	SMARCA5, VAV1, KIF4A, FBN1, JAG1, ARVCF

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SMARCA5	1	—
VAV1	1	—
KIF4A	20	—
FBN1	0	—
HARS1	5	—
JAG1	1	—
KCNA6	29	—
ARVCF	0	—
AIFM1	2	—
PTPRQ	0	—
PTPRR	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 39.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	35
PHASE4	3
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06211504	PHASE4	RECRUITING	Sinus Tarsi Implant as an Adjuvant Procedure to Medial Displacement Calcaneal Osteotomy in the Treatment of Mobile Adult Acquired Flatfoot Deformity
NCT02414087	PHASE4	UNKNOWN	Therapeutic Effects of Customized Insoles on Children With Flat Foot
NCT04564430	PHASE4	UNKNOWN	Clonidine for Tourniquet-related Pain in Children
NCT03918798	PHASE2	COMPLETED	The Efficacy and Safety of Chloroprocaine 1% and 2% in Pediatric Population
NCT04840017	Not specified	ENROLLING_BY_INVITATION	The Influence of Rehabilitation Program on Postural Control, Balance and Gait in Children With Flatfoot
NCT06606392	Not specified	NOT_YET_RECRUITING	Effect of Biodex Balance Training and Short Foot Exercise on Myoelectric Activity of Paraspinal Muscles in Subjects with Flexible Flatfoot
NCT06957353	Not specified	NOT_YET_RECRUITING	Oblique K-wire Control in Calcaneal Osteotomy for Flatfoot Correction
NCT07237321	Not specified	NOT_YET_RECRUITING	Peripheral Magnetic Stimulation of Foot Muscles: Effects on Medial Longitudinal Arch Height and Foot Muscle Strength in Adults With Flat Feet
NCT07238270	Not specified	ACTIVE_NOT_RECRUITING	Research on Physical Fitness and Flatfoot in Children
NCT07515170	Not specified	NOT_YET_RECRUITING	The Corrective Power of Subtalar Arthrodesis With Mini/Medial Bone Block (SAMBB) in Patients Affected by Progressive Collapsing Foot Deformity (PCFD): Analysis Using Weight-bearing Cone Beam CT.
NCT07590297	Not specified	NOT_YET_RECRUITING	Translation, Cross-cultural Adaptation, and Validation of the FPI-6 in Spain
NCT00527748	Not specified	TERMINATED	Foot and Ankle Range of Motion (Stretching) Apparatus
NCT01187693	Not specified	COMPLETED	The Outcome Effect of Shoe Lift for Individuals With Low Back Pain and Pronated Foot Due to Anatomical Leg Length Discrepancy
NCT01645267	Not specified	UNKNOWN	Calcaneal Neck Lengthening Osteotomy With Artificial Bone Graft
NCT02629731	Not specified	COMPLETED	Orthotic Dose Response Study
NCT02706327	Not specified	COMPLETED	Comparison of Two Different Insole Types in Painful Flexible Flatfoot
NCT02957812	Not specified	COMPLETED	The Effects of 12-week Custom-made Orthotic Intervention on the Structure and Function of the Foot of Healthy Young Adults During Gait Termination
NCT03039179	Not specified	COMPLETED	Polyurethane Foam on the Heel for Prevention in Children
NCT03040882	Not specified	COMPLETED	Cotton Sock in Pediatric Patients With Leg-foot Splint
NCT03151538	Not specified	COMPLETED	Effects on Pes Planus Exercise Training Mixed With Play on Pre-school Children
NCT03372642	Not specified	COMPLETED	Effectiveness of Subtalar Arthroereisis With Endorthesis for Pediatric Flexible Flat Foot
NCT03421665	Not specified	WITHDRAWN	Evaluation of the Titan 3-D™ Wedge System
NCT03812822	Not specified	COMPLETED	Describing the Effects of Insoles in Children With Increased Femoral Anteversion and Pes Planovalgus
NCT03843177	Not specified	COMPLETED	Association of Ingrown Toenails With Flat Foot, Hallux Abducto Valgus and Hallux Limitus
NCT04003870	Not specified	COMPLETED	Orthotics and Achilles Load in Runners
NCT05018130	Not specified	UNKNOWN	Bio-Integrative Versus Metallic Screws for Calcaneus Osteotomies
NCT05128526	Not specified	COMPLETED	Short Foot Exercises With Respiratuar Exercises
NCT05381558	Not specified	UNKNOWN	Evaluation of the Role of Local Steroid Injection in Treatment of Idiopathic Spasmodic Flat Foot in Adolescent Patients
NCT05437042	Not specified	COMPLETED	Effect of Medial Wedge on Static Balance in Pronated Feet
NCT05616637	Not specified	COMPLETED	Investigation of Inter-rater and Test-retest Reliability of Y Balance Test in Individuals With Pes Planus
NCT05873166	Not specified	COMPLETED	Stabilometry After Pressure Release of the Flexor Digitorum Brevis Muscle Versus a Non-emission Laser: Clinical Trial
NCT05875415	Not specified	COMPLETED	Dynamic Plantar Pressures Changes After Dry Needling in Flexor Digitorum Brevis Versus Non Emission Laser
NCT05899855	Not specified	UNKNOWN	Foot Positions Affect Knee and Ankle Proprioception, Balance, Vertical Jump, and Muscle Activity in Individuals With Flexible and Rigid Flatfoot and Chronic Ankle Instability
NCT06037746	Not specified	COMPLETED	Immediate Effects of Myofascial Release Techniques on Balance in Young Adults With Pes Planus
NCT06045208	Not specified	COMPLETED	Foot and Lower Extremity Exercises in Adolescents With Pes Planovalgus
NCT06296524	Not specified	UNKNOWN	Effect of Footcore Exercises on Navicular Drop and Plantar Pressure Distribution in Asymptomatic Individual With Flatfoot
NCT06499545	Not specified	COMPLETED	Plantar Pressures After Pressure Release of the Flexor Digitorum Brevis Muscle Versus a Non-emission Laser.
NCT07125781	Not specified	COMPLETED	Central Sensitization and Nociplastic Pain in Pes Planus
NCT07155577	Not specified	COMPLETED	Effects of Pes Planus on Gait at Different Inclines

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CHLOROPROCAINE	4	1
SODIUM CHLORIDE	4	1
DURAPATITE	2	1
COTTON, PURIFIED	-1	1