Linear nevus sebaceous syndrome

Summary

Linear nevus sebaceous syndrome (MONDO:0008097) is a disease caused by KRAS (GenCC Strong), with 4 cohort genes and 3 clinical trials. The dominant Reactome pathway is Signaling by RAS GAP mutants (3 cohort genes). Top therapeutic interventions include burosumab.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: KRAS (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 54
• Phenotypes (HPO): 31
• Clinical trials: 3

Clinical features

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0000269	Prominent occiput	Very frequent (80-99%)
HP:0000506	Telecanthus	Very frequent (80-99%)
HP:0000568	Microphthalmia	Very frequent (80-99%)
HP:0000612	Iris coloboma	Very frequent (80-99%)
HP:0000995	Melanocytic nevus	Very frequent (80-99%)
HP:0001048	Cavernous hemangioma	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001315	Reduced tendon reflexes	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0001596	Alopecia	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0002119	Ventriculomegaly	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0002816	Genu recurvatum	Very frequent (80-99%)
HP:0003422	Vertebral segmentation defect	Very frequent (80-99%)
HP:0004422	Biparietal narrowing	Very frequent (80-99%)
HP:0007360	Aplasia/Hypoplasia of the cerebellum	Very frequent (80-99%)
HP:0009720	Adenoma sebaceum	Very frequent (80-99%)
HP:0100555	Asymmetric growth	Very frequent (80-99%)
HP:0000324	Facial asymmetry	Frequent (30-79%)
HP:0000478	Abnormality of the eye	Frequent (30-79%)
HP:0000504	Abnormality of vision	Frequent (30-79%)
HP:0001357	Plagiocephaly	Frequent (30-79%)
HP:0002132	Porencephaly	Frequent (30-79%)
HP:0007400	Irregular hyperpigmentation	Frequent (30-79%)
HP:0001305	Dandy-Walker malformation	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0002514	Cerebral calcification	Occasional (5-29%)
HP:0007370	Aplasia/Hypoplasia of the corpus callosum	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	linear nevus sebaceous syndrome
Mondo ID	MONDO:0008097
OMIM	163200
Orphanet	2612
DOID	DOID:0111530
NCIT	C4678
UMLS	C4552097
MedGen	1646345
GARD	0010291
NORD	1692
Is cancer (heuristic)	no

Also known as: epidermal nevus syndrome · Jadassohn nevus phakomatosis · JNP · linear sebaceous Nevus · Nevus sebaceous of Jadassohn · Nevus sebaceus of Jadassohn · Nevus Sebaceus Syndrome · Nevus sebaceus syndrome · organoid Nevus · organoid nevus phakomatosis · organoid nevus syndrome · Schimmelpenning Feuerstein Mims syndrome · Schimmelpenning syndrome · SCHIMMELPENNING-FEUERSTEIN-MIMS syndrome · Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic · sebaceous nevus syndrome linear · SFM · SFM syndrome · Solomon syndrome

Data availability: 54 ClinVar variants · 1 GenCC gene-disease record · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › hamartoma › linear nevus sebaceous syndrome

Related subtypes (12): chondroid hamartoma, gastrointestinal hamartoma, linear and whorled nevoid hypermelanosis, congenital epulis, congenital smooth muscle hamartoma, hamartoma of skin appendage, hamartoma of lung, basaloid follicular hamartoma, angiomyomatous hamartoma, giant mammary hamartoma, mesenchymal hamartoma, odontoma

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

54 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 9 pathogenic, 6 conflicting classifications of pathogenicity, 5 pathogenic/likely pathogenic, 4 likely benign, 3 likely pathogenic, 3 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12603	NM_005343.4(HRAS):c.35G>C (p.Gly12Ala)	HRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
12604	NM_005343.4(HRAS):c.38G>A (p.Gly13Asp)	HRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
12606	NM_005343.4(HRAS):c.37G>T (p.Gly13Cys)	HRAS	Pathogenic	reviewed by expert panel
12613	NM_005343.4(HRAS):c.34G>T (p.Gly12Cys)	HRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
35554	NM_005343.4(HRAS):c.37G>C (p.Gly13Arg)	HRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
391700	NM_005343.4(HRAS):c.179G>T (p.Gly60Val)	HRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
12582	NM_004985.5(KRAS):c.35G>A (p.Gly12Asp)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12583	NM_004985.5(KRAS):c.35G>T (p.Gly12Val)	KRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
12587	NM_004985.5(KRAS):c.458A>T (p.Asp153Val)	KRAS	Pathogenic	reviewed by expert panel
376325	NM_033360.4(KRAS):c.64C>A (p.Gln22Lys)	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
180848	NM_005343.4(HRAS):c.38G>T (p.Gly13Val)	LRRC56	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13900	NM_002524.5(NRAS):c.182A>G (p.Gln61Arg)	NRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
160364	NM_005343.4(HRAS):c.182A>G (p.Gln61Arg)	HRAS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4279977	NM_004985.5(KRAS):c.350A>G (p.Lys117Arg)	KRAS	Likely pathogenic	criteria provided, single submitter
13899	NM_002524.5(NRAS):c.37G>C (p.Gly13Arg)	NRAS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
240138	NM_005343.4(HRAS):c.546G>A (p.Met182Ile)	HRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
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
177918	NM_005343.4(HRAS):c.505C>T (p.Arg169Trp)	HRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
180851	NM_005343.4(HRAS):c.367C>T (p.Arg123Cys)	HRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
180856	NM_005343.4(HRAS):c.506G>A (p.Arg169Gln)	HRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
3599788	NM_005343.4(HRAS):c.550T>G (p.Cys184Gly)	HRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
40447	NM_005343.4(HRAS):c.508A>T (p.Lys170Ter)	HRAS	Uncertain significance	reviewed by expert panel
409949	NM_005343.4(HRAS):c.391C>T (p.Gln131Ter)	HRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
409951	NM_005343.4(HRAS):c.398T>A (p.Leu133His)	HRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 24 · 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
KRAS	Strong	Autosomal dominant	linear nevus sebaceous syndrome	17

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
LRRC56	Orphanet:244	Primary ciliary dyskinesia
HRAS	Orphanet:146	Differentiated thyroid carcinoma
HRAS	Orphanet:2612	Linear nevus sebaceus syndrome
HRAS	Orphanet:2874	Phakomatosis pigmentokeratotica
HRAS	Orphanet:3071	Costello syndrome
HRAS	Orphanet:79414	Woolly hair nevus
NRAS	Orphanet:146	Differentiated thyroid carcinoma
NRAS	Orphanet:2612	Linear nevus sebaceus syndrome
NRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease
NRAS	Orphanet:389	Langerhans cell histiocytosis
NRAS	Orphanet:626	Large/giant congenital melanocytic nevus
NRAS	Orphanet:648	Noonan syndrome
NRAS	Orphanet:86834	Juvenile myelomonocytic leukemia

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	gencc,clinvar
LRRC56	HGNC:25430	ENSG00000161328	Q8IYG6	Leucine-rich repeat-containing protein 56	clinvar
HRAS	HGNC:5173	ENSG00000174775	P01112	GTPase HRas	clinvar
NRAS	HGNC:7989	ENSG00000213281	P01111	GTPase NRas	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
LRRC56	Leucine-rich repeat-containing protein 56	Required for the assembly of dynein arms.
HRAS	GTPase HRas	Involved in the activation of Ras protein signal transduction.
NRAS	GTPase NRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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)	2	6.0×	0.074
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
LRRC56	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_4, LRR_dom_sf
HRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
NRAS	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type

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
nipple	1
pylorus	1
trigeminal ganglion	1
left testis	1
right testis	1
right uterine tube	1
skin of abdomen	1
skin of leg	1
zone of skin	1
epithelium of nasopharynx	1
gingival epithelium	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
LRRC56	129	broad	marker	right uterine tube, right testis, left testis
HRAS	139	ubiquitous	marker	skin of abdomen, skin of leg, zone of skin
NRAS	278	ubiquitous	marker	gingival epithelium, epithelium of nasopharynx, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRAS	14,509
HRAS	8,064
NRAS	7,598
LRRC56	914

Intra-cohort edges

A	B	Sources
KRAS	NRAS	intact

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
HRAS	P01112	246
NRAS	P01111	35

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRRC56	Q8IYG6	56.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 73. 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
Signaling by RAS GAP mutants	3	3806.7×	1e-10	KRAS, HRAS, NRAS
Signaling by RAS GTPase mutants	3	3806.7×	1e-10	KRAS, HRAS, NRAS
Activation of RAS in B cells	3	2284.0×	1e-09	KRAS, HRAS, NRAS
RAS signaling downstream of NF1 loss-of-function variants	3	1631.4×	2e-09	KRAS, HRAS, NRAS
Estrogen-stimulated signaling through PRKCZ	3	1631.4×	2e-09	KRAS, HRAS, NRAS
SOS-mediated signalling	3	1427.5×	3e-09	KRAS, HRAS, NRAS
Activated NTRK3 signals through RAS	3	1268.9×	4e-09	KRAS, HRAS, NRAS
EGFR Transactivation by Gastrin	3	1142.0×	4e-09	KRAS, HRAS, NRAS
SHC-related events triggered by IGF1R	3	1142.0×	4e-09	KRAS, HRAS, NRAS
Activated NTRK2 signals through RAS	3	1142.0×	4e-09	KRAS, HRAS, NRAS
MET activates RAS signaling	3	1038.2×	4e-09	KRAS, HRAS, NRAS
Signaling by FGFR4 in disease	3	951.7×	5e-09	KRAS, HRAS, NRAS
Activated NTRK2 signals through FRS2 and FRS3	3	951.7×	5e-09	KRAS, HRAS, NRAS
Constitutive Signaling by Overexpressed ERBB2	3	951.7×	5e-09	KRAS, HRAS, NRAS
p38MAPK events	3	878.5×	5e-09	KRAS, HRAS, NRAS
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	3	878.5×	5e-09	KRAS, HRAS, NRAS
Signaling by PDGFRA extracellular domain mutants	3	878.5×	5e-09	KRAS, HRAS, NRAS
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	3	815.7×	6e-09	KRAS, HRAS, NRAS
GRB2 events in EGFR signaling	3	761.3×	6e-09	KRAS, HRAS, NRAS
Erythropoietin activates RAS	3	761.3×	6e-09	KRAS, HRAS, NRAS
Signaling by FLT3 ITD and TKD mutants	3	761.3×	6e-09	KRAS, HRAS, NRAS
SHC1 events in ERBB4 signaling	3	713.8×	7e-09	KRAS, HRAS, NRAS
SHC1 events in EGFR signaling	3	713.8×	7e-09	KRAS, HRAS, NRAS
Constitutive Signaling by EGFRvIII	3	713.8×	7e-09	KRAS, HRAS, NRAS
Signalling to RAS	3	671.8×	7e-09	KRAS, HRAS, NRAS
Insulin receptor signalling cascade	3	671.8×	7e-09	KRAS, HRAS, NRAS
Signaling by ERBB2 ECD mutants	3	671.8×	7e-09	KRAS, HRAS, NRAS
GRB2 events in ERBB2 signaling	3	634.4×	9e-09	KRAS, HRAS, NRAS
Tie2 Signaling	3	601.0×	1e-08	KRAS, HRAS, NRAS
SHC-mediated cascade:FGFR3	3	601.0×	1e-08	KRAS, HRAS, NRAS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Ras protein signal transduction	3	154.1×	3e-05	KRAS, HRAS, NRAS
MAPK cascade	3	114.9×	4e-05	KRAS, HRAS, NRAS
regulation of long-term neuronal synaptic plasticity	2	495.6×	1e-04	KRAS, HRAS
neuron apoptotic process	2	92.6×	0.003	KRAS, HRAS
response to mineralocorticoid	1	4213.0×	0.003	KRAS
negative regulation of neuron apoptotic process	2	55.4×	0.006	KRAS, HRAS
forebrain astrocyte development	1	1404.3×	0.006	KRAS
positive regulation of miRNA metabolic process	1	1404.3×	0.006	HRAS
response to isolation stress	1	1053.2×	0.007	KRAS
response to gravity	1	702.2×	0.010	KRAS
oncogene-induced cell senescence	1	601.9×	0.011	HRAS
T-helper 1 type immune response	1	468.1×	0.012	HRAS
type I pneumocyte differentiation	1	383.0×	0.014	KRAS
myoblast proliferation	1	351.1×	0.014	KRAS
positive regulation of cellular senescence	1	324.1×	0.014	KRAS
negative regulation of epithelial cell differentiation	1	300.9×	0.014	KRAS
Schwann cell development	1	263.3×	0.014	HRAS
regulation of synaptic transmission, GABAergic	1	263.3×	0.014	KRAS
striated muscle cell differentiation	1	247.8×	0.014	KRAS
positive regulation of ruffle assembly	1	247.8×	0.014	HRAS
glial cell proliferation	1	221.7×	0.014	KRAS
regulation of neurotransmitter receptor localization to postsynaptic specialization membrane	1	221.7×	0.014	HRAS
epithelial tube branching involved in lung morphogenesis	1	210.7×	0.014	KRAS
positive regulation of glial cell proliferation	1	175.5×	0.017	KRAS
positive regulation of Rac protein signal transduction	1	162.0×	0.017	KRAS
defense response to protozoan	1	150.5×	0.017	HRAS
cellular response to gamma radiation	1	150.5×	0.017	HRAS
cardiac muscle cell proliferation	1	145.3×	0.017	KRAS
Rac protein signal transduction	1	140.4×	0.017	KRAS
positive regulation of protein targeting to membrane	1	140.4×	0.017	HRAS

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
HRAS	LONAFARNIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KRAS	11	4
HRAS	4	4
NRAS	1	1
LRRC56	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	KRAS
DABRAFENIB	4	KRAS
LONAFARNIB	4	HRAS, KRAS
SOTORASIB	4	KRAS
ADAGRASIB	4	KRAS
OPNURASIB	3	KRAS
DIVARASIB	2	KRAS
GLECIRASIB	2	KRAS
STALLIMYCIN	2	HRAS
BMS-214662	1	HRAS, KRAS
LY-3009120	1	KRAS
MRTX-1133	1	KRAS
L-778123 FREE BASE	1	HRAS, NRAS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
KRAS	861	Binding:829, Functional:32
HRAS	48	Binding:45, Functional:3
NRAS	18	Binding:18

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KRAS	3.6.5.2	small monomeric GTPase
HRAS	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: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

13 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	HRAS, KRAS
SOTORASIB	4	KRAS
ADAGRASIB	4	KRAS
OPNURASIB	3	KRAS
DIVARASIB	2	KRAS
GLECIRASIB	2	KRAS
STALLIMYCIN	2	HRAS
BMS-214662	1	HRAS, KRAS
LY-3009120	1	KRAS
MRTX-1133	1	KRAS
L-778123 FREE BASE	1	HRAS, NRAS

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	KRAS, HRAS
B	Phased (≥1) drug, not yet approved	1	NRAS
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	LRRC56

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LRRC56	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	1
PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04320316	PHASE4	COMPLETED	A Trial to Assess the Safety and Efficacy of KRN23 in Epidermal Nevus Syndrome (ENS)
NCT02304367	PHASE2	COMPLETED	Study of Burosumab (KRN23) in Adults With Tumor-Induced Osteomalacia (TIO) or Epidermal Nevus Syndrome (ENS)
NCT03993821	EARLY_PHASE1	UNKNOWN	Burosumab for CSHS

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BUROSUMAB	4	2