Cenani-Lenz syndactyly syndrome

Summary

Cenani-Lenz syndactyly syndrome (MONDO:0008931) is a disease caused by LRP4 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LRP4 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 1,285
• Phenotypes (HPO): 41

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)

41 HPO clinical features (Orphanet curated; top 41 by frequency):

HPO ID	Term	Frequency
HP:0001817	Absent fingernail	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0005048	Synostosis of carpal bones	Very frequent (80-99%)
HP:0005916	Abnormal metacarpal morphology	Very frequent (80-99%)
HP:0006101	Finger syndactyly	Very frequent (80-99%)
HP:0012165	Oligodactyly	Very frequent (80-99%)
HP:0100240	Synostosis of joints	Very frequent (80-99%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000494	Downslanted palpebral fissures	Frequent (30-79%)
HP:0001770	Toe syndactyly	Frequent (30-79%)
HP:0001802	Absent toenail	Frequent (30-79%)
HP:0002974	Radioulnar synostosis	Frequent (30-79%)
HP:0002984	Hypoplasia of the radius	Frequent (30-79%)
HP:0003022	Hypoplasia of the ulna	Frequent (30-79%)
HP:0009778	Short thumb	Frequent (30-79%)
HP:0000272	Malar flattening	Occasional (5-29%)
HP:0000322	Short philtrum	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000411	Protruding ear	Occasional (5-29%)
HP:0000444	Convex nasal ridge	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000520	Proptosis	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000656	Ectropion	Occasional (5-29%)
HP:0000668	Hypodontia	Occasional (5-29%)
HP:0000682	Abnormality of dental enamel	Occasional (5-29%)
HP:0000772	Abnormal rib morphology	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0001601	Laryngomalacia	Occasional (5-29%)
HP:0001849	Foot oligodactyly	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002705	High, narrow palate	Occasional (5-29%)
HP:0002827	Hip dislocation	Occasional (5-29%)
HP:0002983	Micromelia	Occasional (5-29%)
HP:0003042	Elbow dislocation	Occasional (5-29%)
HP:0003196	Short nose	Occasional (5-29%)
HP:0003312	Abnormal form of the vertebral bodies	Occasional (5-29%)
HP:0004736	Crossed fused renal ectopia	Occasional (5-29%)
HP:0007477	Abnormal dermatoglyphics	Occasional (5-29%)
HP:0008678	Renal hypoplasia/aplasia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Cenani-Lenz syndactyly syndrome
Mondo ID	MONDO:0008931
MeSH	C538150
OMIM	212780
Orphanet	3258
DOID	DOID:0090015
SNOMED CT	720633009
UMLS	C1859309
MedGen	395226
GARD	0005084
Is cancer (heuristic)	no

Also known as: Cenani syndactyly · Cenani-Lenz syndactyly · Cenani-Lenz syndactyly syndrome · Cenani-Lenz type syndactyly · CLSS · syndactyly Cenani Lenz type · syndactyly type 7

Data availability: 1,285 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › congenital limb malformation › Cenani-Lenz syndactyly syndrome

Related subtypes (106): Adams-Oliver syndrome, ADULT syndrome, Hypoglossia-hypodactyly syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, Cooks syndrome, Townes-Brocks syndrome, brachydactyly-arterial hypertension syndrome, brachydactyly-preaxial hallux varus syndrome, fibular aplasia-ectrodactyly syndrome, Brachymorphism-onychodysplasia-dysphalangism syndrome, brachytelephalangy-dysmorphism-Kallmann syndrome, femoral-facial syndrome, laurin-Sandrow syndrome, Emery-Nelson syndrome, hand-foot-genital syndrome, IVIC syndrome, Leri pleonosteosis, OSLAM syndrome, pelvis-shoulder dysplasia, phocomelia-ectrodactyly-deafness-sinus arrhythmia syndrome, Poland syndrome, crossed polysyndactyly, postaxial tetramelic oligodactyly, radio-renal syndrome, scalp defects-postaxial polydactyly syndrome, splenogonadal fusion-limb defects-micrognathia syndrome, Karsch-Neugebauer syndrome, symphalangism with multiple anomalies of hands and feet, proximal symphalangism, tarsal-carpal coalition syndrome, extensor tendons of finger anomalies, tetramelic monodactyly, thumb stiffness-brachydactyly-intellectual disability syndrome, tibia, hypoplasia or aplasia of, with polydactyly, Say-field-Coldwell syndrome, triphalangeal thumbs-brachyectrodactyly syndrome, humerus trochlea aplasia, Aphalangy-hemivertebrae-urogenital-intestinal dysgenesis syndrome, camptodactyly syndrome, Guadalajara type 2, split hand-foot malformation 1 with sensorineural hearing loss, EEM syndrome, ectrodactyly-polydactyly syndrome, lethal faciocardiomelic dysplasia, femur-fibula-ulna complex, Gollop-Wolfgang complex, acromesomelic dysplasia 2B, Fuhrmann syndrome, hallux varus-preaxial polysyndactyly syndrome, Keutel syndrome, absence deformity of leg-cataract syndrome, intellectual disability-spasticity-ectrodactyly syndrome, fibular aplasia, tibial campomelia, and oligosyndactyly syndrome, pelviscapular dysplasia, radioulnar synostosis-developmental delay-hypotonia syndrome, rapadilino syndrome, EEC syndrome, Sugarman brachydactyly, tetraamelia-multiple malformations syndrome, thrombocytopenia-absent radius syndrome, phocomelia, Schinzel type, ulna hypoplasia-intellectual disability syndrome, syndactyly-telecanthus-anogenital and renal malformations syndrome, Mononen-Karnes-Senac syndrome, absent radius-anogenital anomalies syndrome, ulnar hypoplasia-split foot syndrome, aphalangy-syndactyly-microcephaly syndrome, 2q37 microdeletion syndrome, absent tibia-polydactyly-arachnoid cyst syndrome, skeletal dysplasia-epilepsy-short stature syndrome, autosomal recessive amelia, temtamy preaxial brachydactyly syndrome, radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome, acropectoral syndrome, familial digital arthropathy-brachydactyly, Duane-radial ray syndrome, ulnar/fibula ray defect-brachydactyly syndrome, intellectual disability-brachydactyly-Pierre Robin syndrome, Al-Gazali syndrome, cocoon syndrome, mammary-digital-nail syndrome, syndactyly-camptodactyly and clinodactyly of fifth fingers-bifid toes syndrome, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, split-foot malformation-mesoaxial polydactyly syndrome, TELO2-related intellectual disability-neurodevelopmental disorder, arthrogryposis syndrome, radial deficiency-tibial hypoplasia syndrome, camptodactyly-taurinuria syndrome, fibular dimelia-diplopodia syndrome, shoulder and thorax deformity-congenital heart disease syndrome, Cornelia de Lange syndrome, familial clubfoot with or without associated lower limb anomalies, heart-hand syndrome, hyperphosphatasia-intellectual disability syndrome, limb transversal defect-cardiac anomaly syndrome, triphalangeal thumb-polysyndactyly syndrome, multiple synostoses syndrome, hereditary thrombocytosis with transverse limb defect, thalidomide embryopathy, tibial aplasia-ectrodactyly syndrome, microcephaly-brachydactyly-kyphoscoliosis syndrome, acrofacial dysostosis, caudal regression-sirenomelia spectrum, Rubinstein-Taybi syndrome, acrocephalosyndactyly, congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome, omphalocele-diaphragmatic hernia-cardiovascular anomalies-radial ray defect syndrome

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:

300 uncertain significance, 251 likely benign, 24 conflicting classifications of pathogenicity, 9 benign, 7 benign/likely benign, 4 likely pathogenic, 4 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1180722	NM_002334.4(LRP4):c.3698A>C (p.Glu1233Ala)	LRP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323250	NM_002334.4(LRP4):c.2830C>T (p.Gln944Ter)	LRP4	Pathogenic	criteria provided, multiple submitters, no conflicts
1393202	NM_002334.4(LRP4):c.2260C>T (p.Arg754Ter)	LRP4	Pathogenic	criteria provided, single submitter
2112258	NM_002334.4(LRP4):c.2498del (p.Thr833fs)	LRP4	Pathogenic	criteria provided, single submitter
2921833	NM_002334.4(LRP4):c.1850del (p.Ala617fs)	LRP4	Pathogenic	criteria provided, single submitter
1179057	NM_002334.4(LRP4):c.1560G>A (p.Trp520Ter)	LRP4	Likely pathogenic	criteria provided, single submitter
1179202	NM_002334.4(LRP4):c.1184-1G>A	LRP4	Likely pathogenic	criteria provided, single submitter
2119457	NM_002334.4(LRP4):c.3699+1G>A	LRP4	Likely pathogenic	criteria provided, single submitter
2687873	NM_002334.4(LRP4):c.2814+1G>A	LRP4	Likely pathogenic	criteria provided, single submitter
1032815	NM_002334.4(LRP4):c.4245C>T (p.Asn1415=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1128252	NM_002334.4(LRP4):c.4404T>C (p.Asn1468=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1306610	NM_002334.4(LRP4):c.1654A>T (p.Asn552Tyr)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1460952	NM_002334.4(LRP4):c.2010G>A (p.Thr670=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1500445	NM_002334.4(LRP4):c.1584C>A (p.Thr528=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1512123	NM_002334.4(LRP4):c.1342A>G (p.Ile448Val)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1519697	NM_002334.4(LRP4):c.1633C>T (p.Arg545Trp)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1567023	NM_002334.4(LRP4):c.132C>T (p.Cys44=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1567152	NM_002334.4(LRP4):c.1932C>T (p.Phe644=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1581161	NM_002334.4(LRP4):c.2216-13G>A	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1590124	NM_002334.4(LRP4):c.390T>C (p.Asp130=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194206	NM_002334.4(LRP4):c.1551T>C (p.Ala517=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1946922	NM_002334.4(LRP4):c.2092+18G>A	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2048965	NM_002334.4(LRP4):c.3292T>A (p.Ser1098Thr)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2062110	NM_002334.4(LRP4):c.5087+13A>G	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2079164	NM_002334.4(LRP4):c.3765A>G (p.Pro1255=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211405	NM_002334.4(LRP4):c.3817C>A (p.Arg1273=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
281776	NM_002334.4(LRP4):c.639C>T (p.Asp213=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282957	NM_002334.4(LRP4):c.5660C>G (p.Ser1887Cys)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
284378	NM_002334.4(LRP4):c.4317C>T (p.Ala1439=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285913	NM_002334.4(LRP4):c.2815-6T>G	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 42 · Orphanet: 9 · 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
CORIN	Definitive	Autosomal recessive	Cenani-Lenz syndactyly syndrome	14
LRP4	Definitive	Autosomal recessive	Cenani-Lenz syndactyly syndrome	13
APC	Supportive	Autosomal recessive	Cenani-Lenz syndactyly syndrome	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CORIN	Orphanet:275555	Preeclampsia
LRP4	Orphanet:3152	Sclerosteosis
LRP4	Orphanet:3258	Cenani-Lenz syndrome
LRP4	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
APC	Orphanet:220460	Attenuated familial adenomatous polyposis
APC	Orphanet:261584	5q22 microdeletion syndrome
APC	Orphanet:314022	Gastric adenocarcinoma and proximal polyposis of the stomach
APC	Orphanet:3258	Cenani-Lenz syndrome
APC	Orphanet:873	Desmoid tumor

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
CORIN	HGNC:19012	ENSG00000145244	Q9Y5Q5	Atrial natriuretic peptide-converting enzyme	gencc,clinvar
LRP4	HGNC:6696	ENSG00000134569	O75096	Low-density lipoprotein receptor-related protein 4	gencc,clinvar
APC	HGNC:583	ENSG00000134982	P25054	Adenomatous polyposis coli protein	gencc
LRP4-AS1	HGNC:44128	ENSG00000247675		LRP4 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CORIN	Atrial natriuretic peptide-converting enzyme	Serine-type endopeptidase involved in atrial natriuretic peptide (NPPA) and brain natriuretic peptide (NPPB) processing.
LRP4	Low-density lipoprotein receptor-related protein 4	Mediates SOST-dependent inhibition of bone formation.
APC	Adenomatous polyposis coli protein	Tumor suppressor.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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
Protease	1	9.2×	0.210
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CORIN	Protease	yes		SRCR, Trypsin_dom, LDrepeatLR_classA_rpt
LRP4	Other/Unknown	no		LDLR_classB_rpt, EGF, EGF-like_Ca-bd_dom
APC	Other/Unknown	no		Armadillo, APC_rpt, SAMP
LRP4-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

4 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
medial globus pallidus	2
cardiac muscle of right atrium	1
heart right ventricle	1
myocardium	1
dorsal motor nucleus of vagus nerve	1
ventricular zone	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1
colonic epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
skin of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CORIN	176	tissue_specific	marker	cardiac muscle of right atrium, heart right ventricle, myocardium
LRP4	242	ubiquitous	marker	ventricular zone, dorsal motor nucleus of vagus nerve, medial globus pallidus
APC	297	ubiquitous	marker	substantia nigra pars compacta, substantia nigra pars reticulata, medial globus pallidus
LRP4-AS1	125	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium, skin of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APC	2,903
CORIN	1,291
LRP4	1,250
LRP4-AS1	0

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APC	P25054	31
LRP4	O75096	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CORIN	Q9Y5Q5	70.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 34. 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
APC truncation mutants are not K63 polyubiquitinated	1	3806.7×	0.009	APC
Signaling by AXIN mutants	1	346.1×	0.010	APC
Signaling by CTNNB1 phospho-site mutants	1	346.1×	0.010	APC
Signaling by APC mutants	1	346.1×	0.010	APC
Signaling by AMER1 mutants	1	346.1×	0.010	APC
APC truncation mutants have impaired AXIN binding	1	271.9×	0.010	APC
AXIN missense mutants destabilize the destruction complex	1	271.9×	0.010	APC
Truncations of AMER1 destabilize the destruction complex	1	271.9×	0.010	APC
Signaling by GSK3beta mutants	1	253.8×	0.010	APC
CTNNB1 S33 mutants aren’t phosphorylated	1	253.8×	0.010	APC
CTNNB1 S37 mutants aren’t phosphorylated	1	253.8×	0.010	APC
CTNNB1 S45 mutants aren’t phosphorylated	1	253.8×	0.010	APC
CTNNB1 T41 mutants aren’t phosphorylated	1	253.8×	0.010	APC
Beta-catenin phosphorylation cascade	1	223.9×	0.010	APC
Physiological factors	1	223.9×	0.010	CORIN
Signaling by WNT in cancer	1	200.3×	0.011	APC
Apoptotic cleavage of cellular proteins	1	158.6×	0.012	APC
Apoptotic execution phase	1	158.6×	0.012	APC
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	119.0×	0.015	APC
Ovarian tumor domain proteases	1	92.8×	0.018	APC
Deactivation of the beta-catenin transactivating complex	1	77.7×	0.021	APC
Degradation of beta-catenin by the destruction complex	1	57.7×	0.026	APC
Apoptosis	1	56.0×	0.026	APC
ECM proteoglycans	1	50.1×	0.028	LRP4
Programmed Cell Death	1	48.8×	0.028	APC
Deubiquitination	1	41.4×	0.031	APC
TCF dependent signaling in response to WNT	1	39.2×	0.032	APC
Signaling by WNT	1	37.3×	0.032	APC
Extracellular matrix organization	1	21.0×	0.055	LRP4
Diseases of signal transduction by growth factor receptors and second messengers	1	18.9×	0.059	APC

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
positive regulation of presynaptic membrane organization	1	5617.3×	0.006	LRP4
negative regulation of canonical Wnt signaling pathway	2	78.6×	0.006	LRP4, APC
Wnt signaling pathway	2	66.5×	0.006	LRP4, APC
regulation of systemic arterial blood pressure by atrial natriuretic peptide	1	1872.4×	0.006	CORIN
synaptic assembly at neuromuscular junction	1	1872.4×	0.006	LRP4
regulation of renal sodium excretion	1	1404.3×	0.006	CORIN
regulation of microtubule-based movement	1	936.2×	0.006	APC
postsynaptic membrane assembly	1	802.5×	0.006	LRP4
negative regulation of cell cycle G1/S phase transition	1	802.5×	0.006	APC
positive regulation of protein localization to centrosome	1	802.5×	0.006	APC
negative regulation of cyclin-dependent protein serine/threonine kinase activity	1	702.2×	0.006	APC
amyloid-beta clearance by cellular catabolic process	1	702.2×	0.006	LRP4
regulation of microtubule-based process	1	624.1×	0.006	APC
skeletal muscle acetylcholine-gated channel clustering	1	624.1×	0.006	LRP4
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	624.1×	0.006	LRP4
regulation of attachment of spindle microtubules to kinetochore	1	561.7×	0.006	APC
presynaptic membrane assembly	1	561.7×	0.006	LRP4
heart valve development	1	510.7×	0.006	APC
generation of neurons	1	510.7×	0.006	LRP4
enzyme-linked receptor protein signaling pathway	1	432.1×	0.006	LRP4
positive regulation of pseudopodium assembly	1	432.1×	0.006	APC
negative regulation of axonogenesis	1	432.1×	0.006	LRP4
peptide hormone processing	1	312.1×	0.008	CORIN
endocardial cushion morphogenesis	1	280.9×	0.009	APC
regulation of cardiac conduction	1	280.9×	0.009	CORIN
proximal/distal pattern formation	1	216.1×	0.010	LRP4
positive regulation of Rac protein signal transduction	1	216.1×	0.010	LRP4
negative regulation of ossification	1	208.1×	0.010	LRP4
mitotic spindle assembly checkpoint signaling	1	187.2×	0.011	APC
Rac protein signal transduction	1	187.2×	0.011	LRP4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 4

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CORIN	0	0
LRP4	0	0
APC	0	0
LRP4-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
APC	24	Binding:24

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

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	CORIN
E	Difficult family or no structure, no drug	3	LRP4, APC, LRP4-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CORIN	0	—
LRP4	0	—
APC	24	—
LRP4-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.