Clubfoot

Summary

Clubfoot (MONDO:0007342) is a disease caused by PITX1 (GenCC Strong), with 20 cohort genes and 46 clinical trials. Top therapeutic interventions include sodium chloride.

At a glance

• Causal gene: PITX1 (GenCC Strong)
• Cohort genes: 20
• ClinVar variants: 39
• Clinical trials: 46

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	clubfoot
Mondo ID	MONDO:0007342
MeSH	D003025
OMIM	119800
DOID	DOID:11836
ICD-10-CM	Q66.0
NCIT	C84641
SNOMED CT	397932003
UMLS	C0009081
MedGen	3130
Is cancer (heuristic)	no

Also known as: CCF · club foot · clubbed foot · clubfoot, congenital, with or without deficiency of long bones and/or mirror-IMAGE polydactyly · congenital talipes equinovarus · equinovarus deformity of foot (finding) · talipes · talipes equinovarus

Data availability: 39 ClinVar variants · 3 GenCC gene-disease records · 2 cell lines.

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 › familial clubfoot with or without associated lower limb anomalies › clubfoot

Related subtypes (1): familial clubfoot due to 17q23.1q23.2 microduplication

Subtypes (2): familial clubfoot due to 5q31 microdeletion, familial clubfoot due to PITX1 point mutation

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

39 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 9 likely pathogenic, 7 pathogenic, 6 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
268018	46;XY;t(2;10)(p25;q26)dn		Pathogenic	criteria provided, single submitter
183349	NM_001384125.1(BLTP1):c.1557T>A (p.Tyr519Ter)	BLTP1	Pathogenic	criteria provided, single submitter
523401	NM_001378615.1(CC2D2A):c.1149+1G>A	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56312	NM_001378615.1(CC2D2A):c.4179+1del	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1057	NM_018122.5(DARS2):c.228-21_228-20delinsC	DARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1062	NM_018122.5(DARS2):c.492+2T>C	DARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
400	NM_019892.6(INPP5E):c.1132C>T (p.Arg378Cys)	INPP5E	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
37253	NM_002653.5(PITX1):c.765_799del (p.Ala256fs)	PITX1	Pathogenic	no assertion criteria provided
7505	NM_002653.5(PITX1):c.388G>A (p.Glu130Lys)	PITX1	Pathogenic	criteria provided, single submitter
374012	NM_182943.3(PLOD2):c.2038C>T (p.Arg680Ter)	PLOD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30473	NM_021625.5(TRPV4):c.947G>A (p.Arg316His)	TRPV4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334402	NM_001366521.1(ATP2B1):c.3060+2T>G	ATP2B1	Likely pathogenic	criteria provided, single submitter
1334403	NM_001366521.1(ATP2B1):c.2938G>T (p.Val980Leu)	ATP2B1	Likely pathogenic	criteria provided, single submitter
978640	NM_001384125.1(BLTP1):c.3323+1G>A	BLTP1	Likely pathogenic	criteria provided, single submitter
978675	NM_001384125.1(BLTP1):c.692del (p.Phe231fs)	BLTP1	Likely pathogenic	criteria provided, single submitter
374067	NM_000093.5(COL5A1):c.2903del (p.Pro968fs)	COL5A1	Likely pathogenic	criteria provided, single submitter
1033526	NM_002653.5(PITX1):c.414G>T (p.Lys138Asn)	PITX1	Likely pathogenic	criteria provided, single submitter
2499600	NM_002653.5(PITX1):c.292del (p.Ser98fs)	PITX1	Likely pathogenic	criteria provided, single submitter
4819354	NM_002653.5(PITX1):c.392dup (p.Arg132fs)	PITX1	Likely pathogenic	criteria provided, single submitter
1325843	NM_002653.5(PITX1):c.87del (p.Ala30fs)	PITX1-AS1	Likely pathogenic	criteria provided, single submitter
523500	NM_012330.4(KAT6B):c.5213C>T (p.Thr1738Ile)	KAT6B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
638278	NM_001042424.3(NSD2):c.3295G>A (p.Glu1099Lys)	NSD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
620433	NM_002653.5(PITX1):c.513C>G (p.Tyr171Ter)	PITX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
257000	NM_001009944.3(PKD1):c.7429C>T (p.Arg2477Cys)	PKD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
374011	NM_182943.3(PLOD2):c.1361G>T (p.Gly454Val)	PLOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
12989	NM_000540.3(RYR1):c.7268T>A (p.Met2423Lys)	RYR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
268021	46;X;idic(Y)(q11);t(2;6;12;3)(q24;q23;q12;p13)[21]/46;XY;t(2;6;12;3)dn		Uncertain significance	criteria provided, single submitter
523443	NM_001605.3(AARS1):c.2054T>C (p.Val685Ala)	AARS1	Uncertain significance	criteria provided, single submitter
2573048	NM_002653.5(PITX1):c.551G>C (p.Trp184Ser)	PITX1	Uncertain significance	criteria provided, single submitter
3066116	NM_002653.5(PITX1):c.422G>A (p.Arg141Gln)	PITX1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 49 · 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
PITX1	Strong	Autosomal dominant	familial clubfoot due to PITX1 point mutation	5
HOXD12	Moderate	Autosomal dominant	clubfoot

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PITX1	Orphanet:1275	Brachydactyly-elbow wrist dysplasia syndrome
PITX1	Orphanet:293144	Familial clubfoot due to 5q31 microdeletion
PITX1	Orphanet:293150	Familial clubfoot due to PITX1 point mutation
PITX1	Orphanet:498494	Mirror-image polydactyly
RYR1	Orphanet:169186	Autosomal recessive centronuclear myopathy
RYR1	Orphanet:169189	Autosomal dominant centronuclear myopathy
RYR1	Orphanet:178145	Moderate multiminicore disease with hand involvement
RYR1	Orphanet:324581	Benign Samaritan congenital myopathy
RYR1	Orphanet:33108	Lethal multiple pterygium syndrome
RYR1	Orphanet:423	Malignant hyperthermia of anesthesia
RYR1	Orphanet:424107	Congenital myopathy with myasthenic-like onset
RYR1	Orphanet:466650	Exercise-induced malignant hyperthermia
RYR1	Orphanet:597	Central core disease
RYR1	Orphanet:700188	Calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy
RYR1	Orphanet:98905	Congenital multicore myopathy with external ophthalmoplegia
RYR1	Orphanet:99741	King-Denborough syndrome
NSD2	Orphanet:280	Wolf-Hirschhorn syndrome
KAT6B	Orphanet:3047	Blepharophimosis-intellectual disability syndrome, SBBYS type
KAT6B	Orphanet:85201	Genitopatellar syndrome
TRPV4	Orphanet:1216	Autosomal dominant congenital benign spinal muscular atrophy
TRPV4	Orphanet:263482	Spondyloepimetaphyseal dysplasia, Maroteaux type
TRPV4	Orphanet:2635	Metatropic dysplasia
TRPV4	Orphanet:431255	Scapuloperoneal spinal muscular atrophy
TRPV4	Orphanet:85169	Familial digital arthropathy-brachydactyly
TRPV4	Orphanet:86820	Familial avascular necrosis of femoral head
TRPV4	Orphanet:93304	Autosomal dominant brachyolmia
TRPV4	Orphanet:93314	Spondylometaphyseal dysplasia, Kozlowski type
TRPV4	Orphanet:99937	Autosomal dominant Charcot-Marie-Tooth disease type 2C
PMPCA	Orphanet:1170	Autosomal recessive cerebelloparenchymal disorder type 3
AARS1	Orphanet:228174	Autosomal dominant Charcot-Marie-Tooth disease type 2N
AARS1	Orphanet:33364	Trichothiodystrophy
AARS1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
INPP5E	Orphanet:1454	Joubert syndrome with hepatic defect
INPP5E	Orphanet:220493	Joubert syndrome with ocular defect
INPP5E	Orphanet:475	Isolated Joubert syndrome
INPP5E	Orphanet:75858	MORM syndrome
COL5A1	Orphanet:287	Classical Ehlers-Danlos syndrome
DARS2	Orphanet:137898	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome
BLTP1	Orphanet:610569	KIAA1109-related early lethal congenital brain malformations-arthrogryposis syndrome
CC2D2A	Orphanet:1454	Joubert syndrome with hepatic defect
CC2D2A	Orphanet:2318	Joubert syndrome with oculorenal defect
CC2D2A	Orphanet:564	Meckel syndrome
CC2D2A	Orphanet:791	Retinitis pigmentosa
ATP2B1	Orphanet:528084	Non-specific syndromic intellectual disability
PKD1	Orphanet:730	Autosomal dominant polycystic kidney disease
PKD1	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
PLOD2	Orphanet:2771	Bruck syndrome
PRKD1	Orphanet:276145	Malignant epithelial tumor of salivary glands
PRKD1	Orphanet:708019	Congenital heart defect-ectodermal dysplasia- brachydactyly-telangiectasia syndrome

Cohort genes → proteins

20 cohort genes, 19 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	20

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PITX1	HGNC:9004	ENSG00000069011	P78337	Pituitary homeobox 1	gencc,clinvar
HOXD12	HGNC:5135	ENSG00000170178	P35452	Homeobox protein Hox-D12	gencc
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	clinvar
NSD2	HGNC:12766	ENSG00000109685	O96028	Histone-lysine N-methyltransferase NSD2	clinvar
KAT6B	HGNC:17582	ENSG00000156650	Q8WYB5	Histone acetyltransferase KAT6B	clinvar
TRPV4	HGNC:18083	ENSG00000111199	Q9HBA0	Transient receptor potential cation channel subfamily V member 4	clinvar
PMPCA	HGNC:18667	ENSG00000165688	Q10713	Mitochondrial-processing peptidase subunit alpha	clinvar
AARS1	HGNC:20	ENSG00000090861	P49588	Alanine–tRNA ligase, cytoplasmic	clinvar
INPP5E	HGNC:21474	ENSG00000148384	Q9NRR6	Phosphatidylinositol polyphosphate 5-phosphatase type IV	clinvar
COL5A1	HGNC:2209	ENSG00000130635	P20908	Collagen alpha-1(V) chain	clinvar
UNC13C	HGNC:23149	ENSG00000137766	Q8NB66	Protein unc-13 homolog C	clinvar
WAPL	HGNC:23293	ENSG00000062650	Q7Z5K2	Wings apart-like protein homolog	clinvar
DARS2	HGNC:25538	ENSG00000117593	Q6PI48	Aspartate–tRNA ligase, mitochondrial	clinvar
BLTP1	HGNC:26953	ENSG00000138688	Q2LD37	Bridge-like lipid transfer protein family member 1	clinvar
CC2D2A	HGNC:29253	ENSG00000048342	Q9P2K1	Coiled-coil and C2 domain-containing protein 2A	clinvar
PITX1-AS1	HGNC:48332	ENSG00000224186		PITX1 antisense RNA 1	clinvar
ATP2B1	HGNC:814	ENSG00000070961	P20020	Plasma membrane calcium-transporting ATPase 1	clinvar
PKD1	HGNC:9008	ENSG00000008710	P98161	Polycystin-1	clinvar
PLOD2	HGNC:9082	ENSG00000152952	O00469	Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2	clinvar
PRKD1	HGNC:9407	ENSG00000184304	Q15139	Serine/threonine-protein kinase D1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PITX1	Pituitary homeobox 1	Sequence-specific transcription factor that binds gene promoters and activates their transcription.
HOXD12	Homeobox protein Hox-D12	Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.
RYR1	Ryanodine receptor 1	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules.
NSD2	Histone-lysine N-methyltransferase NSD2	Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at ‘Lys-36’ (H3K36me2).
KAT6B	Histone acetyltransferase KAT6B	Histone acetyltransferase which may be involved in both positive and negative regulation of transcription.
TRPV4	Transient receptor potential cation channel subfamily V member 4	Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity.
PMPCA	Mitochondrial-processing peptidase subunit alpha	Substrate recognition and binding subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins.
AARS1	Alanine–tRNA ligase, cytoplasmic	Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala).
INPP5E	Phosphatidylinositol polyphosphate 5-phosphatase type IV	Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3), phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol 3,5-bispho…
COL5A1	Collagen alpha-1(V) chain	Type V collagen is a member of group I collagen (fibrillar forming collagen).
UNC13C	Protein unc-13 homolog C	May play a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway.
WAPL	Wings apart-like protein homolog	Regulator of sister chromatid cohesion in mitosis which negatively regulates cohesin association with chromatin.
DARS2	Aspartate–tRNA ligase, mitochondrial	Catalyzes the attachment of aspartate to tRNA(Asp) in a two-step reaction: aspartate is first activated by ATP to form Asp-AMP and then transferred to the acceptor end of tRNA(Asp).
BLTP1	Bridge-like lipid transfer protein family member 1	Bridge-like lipid transfer protein that functions as molecular bridges between endoplasmic reticulum and the membranes targeted for lipid delivery.
CC2D2A	Coiled-coil and C2 domain-containing protein 2A	Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.
ATP2B1	Plasma membrane calcium-transporting ATPase 1	Catalyzes the hydrolysis of ATP coupled with the transport of calcium from the cytoplasm to the extracellular space thereby maintaining intracellular calcium homeostasis.
PKD1	Polycystin-1	Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B.
PLOD2	Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2	Forms hydroxylysine residues in -Xaa-Lys-Gly- sequences in collagens.
PRKD1	Serine/threonine-protein kinase D1	Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and tr…

Protein-family classification

Druggable: 9 · Difficult: 5 · Unknown: 6 · Druggable fraction: 0.45

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
Ion channel	2	11.2×	0.096
Protease	2	3.7×	0.239
Transcription factor	5	2.1×	0.239
Enzyme (other)	3	1.8×	0.403
Antibody/Immunoglobulin	1	1.5×	0.607
Kinase	1	1.4×	0.607
Other/Unknown	6	0.5×	0.995

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PITX1	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
HOXD12	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
NSD2	Transcription factor	no	2.1.1.356	PWWP_dom, SET_dom, Znf_RING
KAT6B	Transcription factor	no	2.3.1.48	Znf_PHD, HAT_MYST-type, Histone_H1/H5_H15
TRPV4	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TrpV1-4
PMPCA	Protease	yes	3.4.24.64	Pept_M16_Zn_BS, Peptidase_M16_C, Metalloenz_LuxS/M16
AARS1	Other/Unknown	no		Ala-tRNA-lgiase_IIc, DHHA1_dom, Transl_B-barrel_sf
INPP5E	Enzyme (other)	yes	3.1.3.36	IPPc, Endo/exonu/phosph_ase_sf, INPP5E
COL5A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
UNC13C	Other/Unknown	no		C2_dom, PKC_DAG/PE, MUN_dom
WAPL	Other/Unknown	no		ARM-like, WAPL_dom, ARM-type_fold
DARS2	Enzyme (other)	yes	6.1.1.12	Asp/Asn-tRNA-synth_IIb, GAD-like_sf, Aa-tRNA-synt_II
BLTP1	Other/Unknown	no		BLTP1, BLTP1_N, BLTP1_M
CC2D2A	Protease	yes		C2_dom, CC2D2AN-C2, C2_domain_sf
PITX1-AS1	Other/Unknown	no
ATP2B1	Transcription factor	no	7.2.2.10	P_typ_ATPase, ATPase_P-typ_cation-transptr_N, ATPase_P-typ_cation-transptr_C
PKD1	Antibody/Immunoglobulin	yes		GPS, LRRNT, PC1
PLOD2	Enzyme (other)	yes	1.14.11.4	Procol_lys_dOase, Oxoglu/Fe-dep_dioxygenase_dom, Pro_4_hyd_alph
PRKD1	Kinase	yes	2.7.11.13	Prot_kinase_dom, PH_domain, PKC_DAG/PE

Expression context

Cohort genes with no expression data: 0.

16 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)	20
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower esophagus mucosa	3
ventricular zone	3
oocyte	3
secondary oocyte	3
esophagus mucosa	2
tendon of biceps brachii	2
cortical plate	2
adrenal tissue	2
frontal pole	2
right uterine tube	2
Brodmann (1909) area 23	2
pharyngeal mucosa	1
muscle layer of sigmoid colon	1
vagina	1
gastrocnemius	1
gluteal muscle	1
hindlimb stylopod muscle	1
ganglionic eminence	1
sural nerve	1
cartilage tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PITX1	180	broad	marker	lower esophagus mucosa, esophagus mucosa, pharyngeal mucosa
HOXD12	22	tissue_specific	yes	vagina, muscle layer of sigmoid colon, tendon of biceps brachii
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle
NSD2	281	ubiquitous	marker	ventricular zone, ganglionic eminence, cortical plate
KAT6B	140	ubiquitous	yes	cortical plate, ventricular zone, sural nerve
TRPV4	171	ubiquitous	marker	cartilage tissue, lower esophagus mucosa, olfactory segment of nasal mucosa
PMPCA	276	ubiquitous	marker	right lobe of liver, adrenal tissue, apex of heart
AARS1	301	ubiquitous	marker	endometrium epithelium, type B pancreatic cell, frontal pole
INPP5E	279	ubiquitous	yes	right uterine tube, secondary oocyte, oocyte
COL5A1	248	ubiquitous	marker	stromal cell of endometrium, periodontal ligament, tendon of biceps brachii
UNC13C	174	broad	marker	secondary oocyte, oocyte, endothelial cell
WAPL	298	ubiquitous	marker	secondary oocyte, oocyte, sperm
DARS2	180	ubiquitous	marker	primordial germ cell in gonad, rectum, adrenal tissue
BLTP1	298	ubiquitous	marker	Brodmann (1909) area 23, corpus callosum, postcentral gyrus
CC2D2A	247	ubiquitous	marker	right uterine tube, bronchial epithelial cell, bronchus
PITX1-AS1	190	tissue_specific	yes	buccal mucosa cell, lower esophagus mucosa, esophagus mucosa
ATP2B1	296	ubiquitous	marker	frontal pole, Brodmann (1909) area 23, lateral nuclear group of thalamus
PKD1	290		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PLOD2	288	ubiquitous	marker	tibia, calcaneal tendon, jejunal mucosa
PRKD1	239	ubiquitous	marker	ventricular zone, seminal vesicle, thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PMPCA	3,679
NSD2	3,530
DARS2	3,288
AARS1	3,074
ATP2B1	3,055
COL5A1	2,600
KAT6B	2,214
RYR1	2,177
PRKD1	2,131
WAPL	2,111

Intra-cohort edges

A	B	Sources
AARS1	DARS2	string_interaction
ATP2B1	TRPV4	string_interaction
PKD1	PRKD1	string_interaction
PKD1	TRPV4	string_interaction

Structural data

PDB: 11 · AlphaFold-only: 8 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NSD2	O96028	22
TRPV4	Q9HBA0	19
PKD1	P98161	13
AARS1	P49588	6
KAT6B	Q8WYB5	3
WAPL	Q7Z5K2	3
RYR1	P21817	2
INPP5E	Q9NRR6	1
COL5A1	P20908	1
DARS2	Q6PI48	1
ATP2B1	P20020	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLOD2	O00469	92.63
PMPCA	Q10713	88.46
CC2D2A	Q9P2K1	69.46
PRKD1	Q15139	68.99
HOXD12	P35452	65.09
PITX1	P78337	62.81
UNC13C	Q8NB66	61.64
BLTP1	Q2LD37

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 65. Enrichment computed across 20 evidence-associated genes (15 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 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ARL13B-mediated ciliary trafficking of INPP5E	1	253.8×	0.064	INPP5E
tRNA Aminoacylation	2	38.1×	0.064	AARS1, DARS2
Ion homeostasis	2	27.2×	0.064	RYR1, ATP2B1
Collagen biosynthesis and modifying enzymes	2	22.7×	0.064	COL5A1, PLOD2
Cohesin Loading onto Chromatin	1	76.1×	0.088	WAPL
Establishment of Sister Chromatid Cohesion	1	69.2×	0.088	WAPL
Reduction of cytosolic Ca++ levels	1	63.4×	0.088	ATP2B1
Platelet calcium homeostasis	1	47.6×	0.088	ATP2B1
Synthesis of PIPs at the Golgi membrane	1	42.3×	0.088	INPP5E
Processing of SMDT1	1	42.3×	0.088	PMPCA
Fibronectin matrix formation	1	38.1×	0.088	COL5A1
Mitochondrial calcium ion transport	1	36.2×	0.088	PMPCA
Mitochondrial tRNA aminoacylation	1	34.6×	0.088	DARS2
VxPx cargo-targeting to cilium	1	34.6×	0.088	PKD1
Attachment of bacteria to epithelial cells	1	33.1×	0.088	COL5A1
Cardiac conduction	2	14.5×	0.088	RYR1, ATP2B1
Cilium Assembly	2	14.5×	0.088	INPP5E, CC2D2A
Ion channel transport	2	12.8×	0.088	RYR1, ATP2B1
Muscle contraction	2	10.3×	0.088	RYR1, ATP2B1
Organelle biogenesis and maintenance	2	8.8×	0.088	INPP5E, CC2D2A
Translation	2	8.3×	0.088	AARS1, DARS2
Transport of small molecules	3	5.0×	0.088	RYR1, PMPCA, ATP2B1
Cytosolic tRNA aminoacylation	1	29.3×	0.094	AARS1
Syndecan interactions	1	28.2×	0.094	COL5A1
TRP channels	1	27.2×	0.094	TRPV4
MET activates PTK2 signaling	1	25.4×	0.097	COL5A1
PI Metabolism	1	23.8×	0.099	INPP5E
Sensory processing of sound	1	20.6×	0.110	ATP2B1
Sphingolipid de novo biosynthesis	1	19.0×	0.112	PRKD1
Platelet homeostasis	1	18.6×	0.112	ATP2B1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 19 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
skin development	3	70.0×	0.002	RYR1, COL5A1, PKD1
collagen biosynthetic process	2	110.9×	0.012	COL5A1, PLOD2
calcium ion transport	3	28.6×	0.012	RYR1, TRPV4, PKD1
hyperosmotic salinity response	1	887.0×	0.022	TRPV4
integrin biosynthetic process	1	887.0×	0.022	COL5A1
mitochondrial asparaginyl-tRNA aminoacylation	1	887.0×	0.022	DARS2
metanephric distal tubule morphogenesis	1	887.0×	0.022	PKD1
blood vessel endothelial cell delamination	1	887.0×	0.022	TRPV4
regulation of cytoplasmic translational fidelity	1	887.0×	0.022	AARS1
atrial septum secundum morphogenesis	1	443.5×	0.022	NSD2
alanyl-tRNA aminoacylation	1	443.5×	0.022	AARS1
aspartyl-tRNA aminoacylation	1	443.5×	0.022	DARS2
regulation of skeletal muscle contraction by modulation of calcium ion sensitivity of myofibril	1	443.5×	0.022	PRKD1
vasopressin secretion	1	443.5×	0.022	TRPV4
negative regulation of chromatin binding	1	443.5×	0.022	WAPL
tRNA aminoacylation	1	443.5×	0.022	DARS2
negative regulation of sister chromatid cohesion	1	443.5×	0.022	WAPL
positive regulation of striated muscle contraction	1	443.5×	0.022	TRPV4
regulation of response to osmotic stress	1	443.5×	0.022	TRPV4
nitrogen cycle metabolic process	1	443.5×	0.022	PKD1
mesonephric tubule development	1	443.5×	0.022	PKD1
calcium ion import into cytosol	1	443.5×	0.022	TRPV4
negative regulation of endodermal cell differentiation	1	443.5×	0.022	COL5A1
regulation of cytosolic calcium ion concentration	2	40.3×	0.022	RYR1, ATP2B1
response to hypoxia	3	15.1×	0.022	RYR1, TRPV4, PLOD2
branchiomeric skeletal muscle development	1	295.6×	0.024	PITX1
lymph vessel morphogenesis	1	295.6×	0.024	PKD1
obsolete hydroxylysine biosynthetic process	1	295.6×	0.024	PLOD2
dense core granule priming	1	295.6×	0.024	UNC13C
cellular hypotonic salinity response	1	295.6×	0.024	TRPV4

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 16

Druggability breadth: 11 of 20 evidence-associated genes (55%) 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
NSD2	VENETOCLAX
PRKD1	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKD1	26	4
NSD2	8	4
TRPV4	6	3
WAPL	1	2
PITX1	0	0
HOXD12	0	0
RYR1	0	0
KAT6B	0	0
PMPCA	0	0
AARS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VENETOCLAX	4	NSD2
MITOXANTRONE	4	NSD2
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
CRIZOTINIB	4	PRKD1
GEFITINIB	4	PRKD1
SURAMIN	3	NSD2, PRKD1
CANNABINOL	3	TRPV4
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
SINEFUNGIN	2	NSD2
MOLIBRESIB	2	NSD2, WAPL
HOMIDIUM BROMIDE	2	NSD2
TETRAHYDROCANNABIVARIN	2	TRPV4
CANNABIDIVARIN	2	TRPV4
GSK2798745	2	TRPV4
CANNABIGEROL	2	TRPV4
PHORBOL MYRISTATE ACETATE	2	PRKD1
EDELFOSINE	2	PRKD1
UPROSERTIB	2	PRKD1
UCN-01	2	PRKD1
SU-014813	2	PRKD1
AT-9283	2	PRKD1
BI-2536	2	PRKD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 8.

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

Symbol	Assays	Type breakdown
PRKD1	660	Binding:650, Functional:10
NSD2	264	Binding:256, Functional:8
TRPV4	99	Binding:94, Functional:5
PKD1	27	Binding:27
KAT6B	22	Binding:20, Functional:2
RYR1	16	Binding:13, Functional:3
WAPL	6	Binding:6
AARS1	2	Binding:2
PLOD2	2	Binding:2
PMPCA	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NSD2	2.1.1.356, 2.1.1.357, 2.1.1.359	[histone H3]-lysine27 N-trimethyltransferase, [histone H3]-lysine36 N-dimethyltransferase, [histone H3]-lysine36 N-trimethyltransferase
KAT6B	2.3.1.48	histone acetyltransferase
PMPCA	3.4.24.64	mitochondrial processing peptidase
INPP5E	3.1.3.36	phosphoinositide 5-phosphatase
DARS2	6.1.1.12	aspartate-tRNA ligase
ATP2B1	7.2.2.10	P-type Ca2+ transporter
PLOD2	1.14.11.4, 2.4.1.50	procollagen-lysine 5-dioxygenase, procollagen galactosyltransferase
PRKD1	2.7.11.13	protein kinase C

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NSD2	264
PRKD1	660

Pharmacogenomics

Cohort genes with a PharmGKB record: 19; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

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)
VENETOCLAX	4	NSD2
MITOXANTRONE	4	NSD2
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
CRIZOTINIB	4	PRKD1
GEFITINIB	4	PRKD1
SURAMIN	3	NSD2, PRKD1
CANNABINOL	3	TRPV4
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
SINEFUNGIN	2	NSD2
MOLIBRESIB	2	NSD2, WAPL
HOMIDIUM BROMIDE	2	NSD2
TETRAHYDROCANNABIVARIN	2	TRPV4
CANNABIDIVARIN	2	TRPV4
GSK2798745	2	TRPV4
CANNABIGEROL	2	TRPV4
PHORBOL MYRISTATE ACETATE	2	PRKD1
EDELFOSINE	2	PRKD1
UPROSERTIB	2	PRKD1
UCN-01	2	PRKD1
SU-014813	2	PRKD1
AT-9283	2	PRKD1
BI-2536	2	PRKD1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	NSD2, PRKD1
B	Phased (≥1) drug, not yet approved	2	TRPV4, WAPL
C	Druggable family + PDB, no drug	4	RYR1, INPP5E, DARS2, PKD1
D	Druggable family + AlphaFold only, no drug	3	PMPCA, CC2D2A, PLOD2
E	Difficult family or no structure, no drug	9	PITX1, HOXD12, KAT6B, AARS1, COL5A1, UNC13C, BLTP1, PITX1-AS1, ATP2B1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PKD1	27	PRKD1
PITX1	0	—
HOXD12	0	—
RYR1	16	—
KAT6B	22	—
PMPCA	1	—
AARS1	2	—
INPP5E	0	—
COL5A1	0	—
UNC13C	0	—
DARS2	0	—
BLTP1	0	—
CC2D2A	0	—
PITX1-AS1	0	—
ATP2B1	0	—
PLOD2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 46.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	43
PHASE4	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04564430	PHASE4	UNKNOWN	Clonidine for Tourniquet-related Pain in Children
NCT04766684	PHASE4	COMPLETED	Clubfoot Tenotomy Trial
NCT02815215	EARLY_PHASE1	UNKNOWN	Efficacy Analysis of Minimally Invasive Carroll’s Technique in Treatment of Congenital Idiopathic Clubfoot
NCT05767762	Not specified	RECRUITING	Evertor Muscle Activity as a Predictor of Achilles Tenotomy in the Management of Idiopathic Varus Equinus Clubfoot
NCT06050746	Not specified	ACTIVE_NOT_RECRUITING	Predictive Value of the PBS-score in Children With Clubfoot
NCT06906406	Not specified	RECRUITING	Health-Related Quality of Life in Children and Adolescents With Clubfoot
NCT07055672	Not specified	ACTIVE_NOT_RECRUITING	Clinical Effectiveness of the Modified WalkFlex DB Splint in Children With Congenital Talipes Equinovarus (CTEV)
NCT07125794	Not specified	RECRUITING	Original Denis Brawn Brace Versus Its Modification for Management of Relapsed Idiopathic Clubfoot Following Ponseti Casting
NCT07154550	Not specified	RECRUITING	Comparing Outcomes and Complications Following Mastisol Application for Clubfoot Casting
NCT07428902	Not specified	RECRUITING	Effects Of French Method With/Without Brace In Clubfoot Treatment
NCT07466043	Not specified	NOT_YET_RECRUITING	Midfoot Osteotomy Versus 8-Plate Epiphysiodesis for Residual Metatarsal Adductus
NCT07473908	Not specified	NOT_YET_RECRUITING	Ultrasound Assessment of Achilles Tendon-Neurovascular Distance in Infants With Unilateral Clubfoot
NCT07554092	Not specified	RECRUITING	Comparison of Radiological Outcome of Conventional vs Accelerated Ponseti Casting Technique for Treatment of Club Foot
NCT07561697	Not specified	RECRUITING	Percutaneous Achilles Tendon Tenotomy vs Tendo-Achilles Lengthening (TAL) in Neglected Clubfoot Children.
NCT07561736	Not specified	RECRUITING	Comparison of Surgical Blade No. 11 and Ophthalmic Knife in Idiopathic Clubfoot Patients
NCT00175708	Not specified	COMPLETED	Pedobarographic Assessments of Clubfoot Treated Patients
NCT00474032	Not specified	UNKNOWN	Using Botox to Treat Patients With Idiopathic Clubfoot
NCT00474344	Not specified	COMPLETED	Genetic Linkage Study of Idiopathic Talipes Equinovarus (ITEV) (Clubfoot)
NCT00475631	Not specified	WITHDRAWN	Economic Evaluation of Clubfoot Treatment: One Centre’s Experience
NCT00607191	Not specified	COMPLETED	Clubfoot DNA Repository
NCT01050088	Not specified	UNKNOWN	Sucrose Analgesia in Infants Undergoing Casting for Club Foot
NCT01067651	Not specified	COMPLETED	Comparison of Casting Materials for the Treatment of Clubfoot Using the Ponseti Method
NCT01088828	Not specified	COMPLETED	Exploring the Causes of Clubfoot Using Magnetic Resonance Imaging, MRI
NCT01481324	Not specified	COMPLETED	Outcomes of Compliance With Brace Wear in Clubfoot
NCT02022267	Not specified	COMPLETED	Gait Analysis in Ponseti Clubfoot
NCT02395185	Not specified	COMPLETED	A Randomized Controlled Trial of Three Non-pharmacologic Analgesic Techniques for Casting of Clubfoot Infants
NCT02815306	Not specified	COMPLETED	Polyaxial Brace Fixing for the Treatment of Congenital Clubfoot
NCT03249805	Not specified	UNKNOWN	MiracleFeet Foot Abduction Brace Sensor Trial
NCT03580746	Not specified	WITHDRAWN	Comparison of Ponseti Method Versus Older Treatments in Talipes Equinovarus Through Gait Analysis and Clinical Results
NCT03671863	Not specified	COMPLETED	Children Born With Club Feet
NCT03749265	Not specified	UNKNOWN	Rate Of Residual Clubfoot Deformity With Correlation To Absence Of Peroneus Tertius Muscle
NCT03853811	Not specified	TERMINATED	Customized Orthosis for Children With Clubfoot
NCT03953430	Not specified	COMPLETED	Gait Analysis in Children With Clubfoot Treated With Tibialis Anterior Tendon Transfer
NCT04212663	Not specified	UNKNOWN	A Study on the Treatment of Recurrent Clubfoot With the Tendon Release of Musculi Tibialis Posterior
NCT04693065	Not specified	UNKNOWN	Pronostic Factors of Long Term Outcome in Patients With Clubfoot Treated by the Ponseti Method
NCT04737083	Not specified	UNKNOWN	CGH Array in Bilateral Clubfoot
NCT04897100	Not specified	COMPLETED	Outcome After Needle vs Blade Achilles Tenotomy in Clubfoot
NCT05293743	Not specified	COMPLETED	Novel Dynamic Foot Abduction Bar for Treatment of Clubfoot
NCT05456737	Not specified	COMPLETED	Functional Assessment in Children With Clubfoot
NCT05794334	Not specified	COMPLETED	Low Dye Taping Technique Versus Robert Debre Method On Foot Posture And Range Of Motion In Children With Club Foot.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SODIUM CHLORIDE	4	1