Toriello-Lacassie-Droste syndrome

Summary

Toriello-Lacassie-Droste syndrome (MONDO:0010854) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 26
• Phenotypes (HPO): 36

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		19	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0000502	Abnormal conjunctiva morphology	Very frequent (80-99%)
HP:0001140	Limbal dermoid	Very frequent (80-99%)
HP:0001274	Agenesis of corpus callosum	Very frequent (80-99%)
HP:0001331	Absent septum pellucidum	Very frequent (80-99%)
HP:0007440	Generalized hyperpigmentation	Very frequent (80-99%)
HP:0008065	Aplasia/Hypoplasia of the skin	Very frequent (80-99%)
HP:0012639	Abnormal nervous system morphology	Very frequent (80-99%)
HP:0000069	Abnormality of the ureter	Frequent (30-79%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000506	Telecanthus	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0000581	Blepharophimosis	Frequent (30-79%)
HP:0000598	Abnormality of the ear	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001561	Polyhydramnios	Frequent (30-79%)
HP:0001626	Abnormality of the cardiovascular system	Frequent (30-79%)
HP:0002251	Aganglionic megacolon	Frequent (30-79%)
HP:0003196	Short nose	Frequent (30-79%)
HP:0004279	Short palm	Frequent (30-79%)
HP:0008749	Laryngeal hypoplasia	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012745	Short palpebral fissure	Frequent (30-79%)
HP:0030680	Abnormal cardiovascular system morphology	Frequent (30-79%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000625	Eyelid coloboma	Occasional (5-29%)
HP:0001999	Abnormal facial shape	Occasional (5-29%)
HP:0000014	Abnormality of the bladder	Occasional (5-29%)
HP:0000036	Abnormality of the penis	Occasional (5-29%)
HP:0000039	Epispadias	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Toriello-Lacassie-Droste syndrome
Mondo ID	MONDO:0010854
MeSH	C563969
OMIM	600268
Orphanet	3339
DOID	DOID:0111705
ICD-11	1983176633
SNOMED CT	723554006
UMLS	C1838329
MedGen	333068
GARD	0010366
Is cancer (heuristic)	no

Also known as: aplasia cutis congenita-epibulbar dermoids syndrome · oculo-ectodermal syndrome · oculoectodermal syndrome · oculoectodermal syndrome, somatic · oes · Toriello Lacassie Droste syndrome

Data availability: 26 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › ectodermal dysplasia syndrome › Toriello-Lacassie-Droste syndrome

Related subtypes (119): ADULT syndrome, autosomal dominant palmoplantar keratoderma and congenital alopecia, ameloonychohypohidrotic syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, anonychia with flexural pigmentation, Böök syndrome, blepharocheilodontic syndrome, Stern-Lubinsky-Durrie syndrome, dermatopathia pigmentosa reticularis, dermo-odonto dysplasia, Rapp-Hodgkin syndrome, Clouston syndrome, ectodermal dysplasia, trichoodontoonychial type, gingival fibromatosis-hypertrichosis syndrome, hypertrichosis cubiti-short stature syndrome, Johnson neuroectodermal syndrome, Marshall syndrome, Naegeli-Franceschetti-Jadassohn syndrome, oculodentodigital dysplasia, Cronkhite-Canada syndrome, scalp-ear-nipple syndrome, tooth and nail syndrome, tricho-dento-osseous syndrome, tricho-retino-dento-digital syndrome, acrofacial dysostosis, Weyers type, Ackerman syndrome, alopecia - contractures - dwarfism - intellectual disability syndrome, AREDYLD syndrome, Barber-Say syndrome, oculoosteocutaneous syndrome, cataract-hypertrichosis-intellectual disability syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, cerebellar ataxia-ectodermal dysplasia syndrome, cranioectodermal dysplasia, conductive deafness-ptosis-skeletal anomalies syndrome, dermatoosteolysis, Kirghizian type, Dubowitz syndrome, ectodermal dysplasia-sensorineural deafness syndrome, ectodermal dysplasia-intellectual disability-central nervous system malformation syndrome, hypohidrotic ectodermal dysplasia-hypothyroidism-ciliary dyskinesia syndrome, cleft lip/palate-ectodermal dysplasia syndrome, EEM syndrome, Ellis-van Creveld syndrome, amelocerebrohypohidrotic syndrome, GAPO syndrome, ichthyosis-alopecia-eclabion-ectropion-intellectual disability syndrome, Leukomelanoderma-infantilism-intellectual disability-hypodontia-hypotrichosis syndrome, Dahlberg-Borer-Newcomer syndrome, cartilage-hair hypoplasia, oculotrichodysplasia, pilodental dysplasia-refractive errors syndrome, Bartsocas-Papas syndrome 1, ectodermal dysplasia-blindness syndrome, Schinzel-Giedion syndrome, Teebi-Shaltout syndrome, taurodontia-absent teeth-sparse hair syndrome, odontotrichomelic syndrome, trichomegaly-retina pigmentary degeneration-dwarfism syndrome, trichoodontoonychial dysplasia, CHIME syndrome, anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome, Ito hypomelanosis, contractures-ectodermal dysplasia-cleft lip/palate syndrome, incontinentia pigmenti, odontomicronychial dysplasia, ectodermal dysplasia with natal teeth, Turnpenny type, hidrotic ectodermal dysplasia, Christianson-Fourie type, trichodental syndrome, congenital hypotrichosis with juvenile macular dystrophy, tricho-oculo-dermo-vertebral syndrome, odonto-tricho-ungual-digito-palmar syndrome, Fried’s tooth and nail syndrome, limb-mammary syndrome, epidermolysis bullosa simplex due to plakophilin deficiency, arrhythmogenic cardiomyopathy with wooly hair and keratoderma, Curly hair - acral keratoderma - caries syndrome, hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma syndrome, Lelis syndrome, Fontaine progeroid syndrome, ectodermal dysplasia-syndactyly syndrome, ectodermal dysplasia 5, hair/nail type, nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome, ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, cardiofaciocutaneous syndrome, choroidal atrophy-alopecia syndrome, dyskeratosis congenita, hidrotic ectodermal dysplasia, Halal type, hypertrichosis lanuginosa congenita, hypohidrotic ectodermal dysplasia, odonto-onycho dysplasia-alopecia syndrome, pili torti-onychodysplasia syndrome, chondroectodermal dysplasia with night blindness, trichorhinophalangeal syndrome, trichothiodystrophy, trichodermodysplasia-dental alterations syndrome, autosomal dominant trichoodontoonychodysplasia-syndactyly, focal facial dermal dysplasia, KID syndrome, pure hair and nail ectodermal dysplasia, circumscribed palmoplantar hypokeratosis, trichodysplasia-amelogenesis imperfecta syndrome, dermotrichic syndrome, alves Castelo dos Santos syndrome, Brunoni syndrome, ectodermal dysplasia Bartalos type, ectodermal dysplasia margarita type, ectodermal dysplasia alopecia preaxial polydactyly, ectodermal dysplasia arthrogryposis diabetes mellitus, ectodermal dysplasia blindness, ectodermal dysplasia neurosensory deafness, ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis, ectodermal dysplasia 15, hypohidrotic/hair type, linear hypopigmentation and craniofacial asymmetry with acral, ocular and brain anomalies, jones hersh yusk syndrome, ectodermal dysplasia 13, hair/tooth type, arthrogryposis-ectodermal dysplasia-other anomalies syndrome, ectodermal dysplasia WNT10A related, CTSC-related disorder, ectodermal dysplasia 17 with or without limb malformations

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

26 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 5 conflicting classifications of pathogenicity, 4 likely benign, 2 pathogenic/likely pathogenic, 2 pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
224333	NM_015041.3(CLUAP1):c.817C>T (p.Leu273Phe)	CLUAP1	Pathogenic	criteria provided, single submitter
12582	NM_004985.5(KRAS):c.35G>A (p.Gly12Asp)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40452	NM_004985.5(KRAS):c.65A>G (p.Gln22Arg)	KRAS	Pathogenic	reviewed by expert panel
45122	NM_004985.5(KRAS):c.35G>C (p.Gly12Ala)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180857	NM_004985.5(KRAS):c.184GAG[1] (p.Glu63del)	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2454057	NM_004985.5(KRAS):c.168C>T (p.Leu56=)	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
503538	NM_004985.5(KRAS):c.407G>A (p.Ser136Asn)	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
620625	NM_033360.4(KRAS):c.*101_*106del	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626130	NM_033360.4(KRAS):c.112-5C>T	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1046139	NM_004985.5(KRAS):c.388_389delinsAT (p.Ala130Ile)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1047419	NM_004985.5(KRAS):c.352T>C (p.Cys118Arg)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1717054	NM_004985.5(KRAS):c.365C>G (p.Ser122Cys)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
180861	NM_033360.4(KRAS):c.389C>T (p.Ala130Val)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1915455	NM_004985.5(KRAS):c.450+5G>A	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
2909102	NM_004985.5(KRAS):c.331A>G (p.Met111Val)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
3574545	NM_004985.5(KRAS):c.451-6T>C	KRAS	Uncertain significance	criteria provided, single submitter
931154	NM_004985.5(KRAS):c.534_536del (p.Lys180del)	KRAS	Uncertain significance	criteria provided, single submitter
935432	NM_004985.5(KRAS):c.487A>G (p.Ile163Val)	KRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
222985	NC_000019.10:g.56032687C>T	NLRP5	Uncertain significance	no assertion criteria provided
222986	NC_000019.10:g.56040975T>C	NLRP5	Uncertain significance	criteria provided, single submitter
138061	NM_033360.4(KRAS):c.90C>T (p.Asp30=)	KRAS	Likely benign	reviewed by expert panel
177714	NM_004985.5(KRAS):c.112-9C>T	KRAS	Likely benign	criteria provided, multiple submitters, no conflicts
180052	NM_004985.5(KRAS):c.451-5652C>T	KRAS	Likely benign	criteria provided, multiple submitters, no conflicts
379556	NM_033360.4(KRAS):c.5-18A>G	KRAS	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
45119	NM_004985.5(KRAS):c.24A>G (p.Val8=)	KRAS	Likely benign	reviewed by expert panel
496491	NM_033360.4(KRAS):c.4+5G>A	KRAS	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRAS	Orphanet:1333	Familial pancreatic carcinoma
KRAS	Orphanet:1340	Cardiofaciocutaneous syndrome
KRAS	Orphanet:144	Lynch syndrome
KRAS	Orphanet:146	Differentiated thyroid carcinoma
KRAS	Orphanet:2396	Encephalocraniocutaneous lipomatosis
KRAS	Orphanet:251615	Pilomyxoid astrocytoma
KRAS	Orphanet:2612	Linear nevus sebaceus syndrome
KRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease
KRAS	Orphanet:3339	Oculoectodermal syndrome
KRAS	Orphanet:648	Noonan syndrome
KRAS	Orphanet:86834	Juvenile myelomonocytic leukemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IFT38	HGNC:19009	ENSG00000103351	Q96AJ1	Clusterin-associated protein 1	clinvar
NLRP5	HGNC:21269	ENSG00000171487	P59047	NACHT, LRR and PYD domains-containing protein 5	clinvar
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IFT38	Clusterin-associated protein 1	Required for cilia biogenesis.
NLRP5	NACHT, LRR and PYD domains-containing protein 5	Component of the subcortical maternal complex (SCMC), a multiprotein complex that plays a key role in early embryonic development.
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IFT38	Other/Unknown	no		Clusterin-associated_protein-1
NLRP5	Other/Unknown	no		Leu-rich_rpt, DAPIN, NACHT_NTPase
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	1
calcaneal tendon	1
epithelium of bronchus	1
male germ line stem cell (sensu Vertebrata) in testis	1
oocyte	1
secondary oocyte	1
nipple	1
pylorus	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IFT38	285	ubiquitous	marker	bronchial epithelial cell, calcaneal tendon, epithelium of bronchus
NLRP5	22		marker	secondary oocyte, oocyte, male germ line stem cell (sensu Vertebrata) in testis
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRAS	14,509
IFT38	1,883
NLRP5	1,057

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
NLRP5	P59047	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IFT38	Q96AJ1	78.02

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 72. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by RAS GAP mutants	1	1903.3×	0.006	KRAS
Signaling by RAS GTPase mutants	1	1903.3×	0.006	KRAS
Activation of RAS in B cells	1	1142.0×	0.006	KRAS
RAS signaling downstream of NF1 loss-of-function variants	1	815.7×	0.006	KRAS
Estrogen-stimulated signaling through PRKCZ	1	815.7×	0.006	KRAS
SOS-mediated signalling	1	713.8×	0.006	KRAS
Activated NTRK3 signals through RAS	1	634.4×	0.006	KRAS
EGFR Transactivation by Gastrin	1	571.0×	0.006	KRAS
SHC-related events triggered by IGF1R	1	571.0×	0.006	KRAS
RUNX3 regulates p14-ARF	1	571.0×	0.006	KRAS
Activated NTRK2 signals through RAS	1	571.0×	0.006	KRAS
MET activates RAS signaling	1	519.1×	0.006	KRAS
Signaling by FGFR4 in disease	1	475.8×	0.006	KRAS
Activated NTRK2 signals through FRS2 and FRS3	1	475.8×	0.006	KRAS
Constitutive Signaling by Overexpressed ERBB2	1	475.8×	0.006	KRAS
p38MAPK events	1	439.2×	0.006	KRAS
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	439.2×	0.006	KRAS
Signaling by PDGFRA extracellular domain mutants	1	439.2×	0.006	KRAS
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	1	407.9×	0.006	KRAS
GRB2 events in EGFR signaling	1	380.7×	0.006	KRAS
Erythropoietin activates RAS	1	380.7×	0.006	KRAS
Signaling by FLT3 ITD and TKD mutants	1	380.7×	0.006	KRAS
SHC1 events in ERBB4 signaling	1	356.9×	0.006	KRAS
SHC1 events in EGFR signaling	1	356.9×	0.006	KRAS
Constitutive Signaling by EGFRvIII	1	356.9×	0.006	KRAS
Signalling to RAS	1	335.9×	0.006	KRAS
Insulin receptor signalling cascade	1	335.9×	0.006	KRAS
Signaling by ERBB2 ECD mutants	1	335.9×	0.006	KRAS
GRB2 events in ERBB2 signaling	1	317.2×	0.006	KRAS
Tie2 Signaling	1	300.5×	0.006	KRAS

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
response to mineralocorticoid	1	5617.3×	0.005	KRAS
cortical granule exocytosis	1	2808.7×	0.005	NLRP5
floor plate formation	1	1872.4×	0.005	IFT38
forebrain astrocyte development	1	1872.4×	0.005	KRAS
establishment of organelle localization	1	1872.4×	0.005	NLRP5
response to isolation stress	1	1404.3×	0.006	KRAS
protein storage	1	1123.5×	0.006	NLRP5
response to gravity	1	936.2×	0.006	KRAS
establishment of spindle localization	1	936.2×	0.006	NLRP5
type I pneumocyte differentiation	1	510.7×	0.009	KRAS
myoblast proliferation	1	468.1×	0.009	KRAS
positive regulation of cellular senescence	1	432.1×	0.009	KRAS
negative regulation of epithelial cell differentiation	1	401.2×	0.009	KRAS
positive regulation of embryonic development	1	374.5×	0.009	NLRP5
regulation of synaptic transmission, GABAergic	1	351.1×	0.009	KRAS
regulation of long-term neuronal synaptic plasticity	1	330.4×	0.009	KRAS
striated muscle cell differentiation	1	330.4×	0.009	KRAS
glial cell proliferation	1	295.6×	0.009	KRAS
intraciliary anterograde transport	1	295.6×	0.009	IFT38
epithelial tube branching involved in lung morphogenesis	1	280.9×	0.009	KRAS
regulation of cell division	1	255.3×	0.009	NLRP5
positive regulation of glial cell proliferation	1	234.1×	0.009	KRAS
positive regulation of Rac protein signal transduction	1	216.1×	0.010	KRAS
cardiac muscle cell proliferation	1	193.7×	0.010	KRAS
Rac protein signal transduction	1	187.2×	0.010	KRAS
axoneme assembly	1	181.2×	0.010	IFT38
homeostasis of number of cells within a tissue	1	147.8×	0.012	KRAS
skeletal muscle cell differentiation	1	114.6×	0.015	KRAS
response to glucocorticoid	1	108.0×	0.015	KRAS
visual learning	1	102.1×	0.016	KRAS

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
KRAS	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KRAS	11	4
IFT38	0	0
NLRP5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	KRAS
DABRAFENIB	4	KRAS
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS
ADAGRASIB	4	KRAS
OPNURASIB	3	KRAS
DIVARASIB	2	KRAS
GLECIRASIB	2	KRAS
BMS-214662	1	KRAS
LY-3009120	1	KRAS
MRTX-1133	1	KRAS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KRAS	861	Binding:829, Functional:32

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KRAS	3.6.5.2	small monomeric GTPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
KRAS	861

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

11 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)
VEMURAFENIB	4	KRAS
DABRAFENIB	4	KRAS
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS
ADAGRASIB	4	KRAS
OPNURASIB	3	KRAS
DIVARASIB	2	KRAS
GLECIRASIB	2	KRAS
BMS-214662	1	KRAS
LY-3009120	1	KRAS
MRTX-1133	1	KRAS

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KRAS
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	IFT38, NLRP5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
IFT38	0	—
NLRP5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.