Large congenital melanocytic nevus

Summary

Large congenital melanocytic nevus (MONDO:0044792) is a disease caused by BRAF (GenCC Strong), with 4 cohort genes and 5 clinical trials. The dominant Reactome pathway is RAF activation (3 cohort genes). Molecularly, AKAP9::BRAF Fusion confers sensitivity to Trametinib in Large Congenital Melanocytic Nevus (CIViC Level C). Top therapeutic interventions include alcohol and squaric acid dibutyl ester.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: BRAF (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 29
• Phenotypes (HPO): 21
• Clinical trials: 5
• Precision-medicine evidence (CIViC): 1 subtype–drug association

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2.75	Europe	Validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0001000	Abnormality of skin pigmentation	Very frequent (80-99%)
HP:0003764	Nevus	Very frequent (80-99%)
HP:0005600	Congenital giant melanocytic nevus	Very frequent (80-99%)
HP:0000958	Dry skin	Frequent (30-79%)
HP:0000970	Anhidrosis	Frequent (30-79%)
HP:0001058	Poor wound healing	Frequent (30-79%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000989	Pruritus	Occasional (5-29%)
HP:0000998	Hypertrichosis	Occasional (5-29%)
HP:0001053	Hypopigmented skin patches	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001482	Subcutaneous nodule	Occasional (5-29%)
HP:0002176	Spinal cord compression	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002516	Increased intracranial pressure	Occasional (5-29%)
HP:0012056	Cutaneous melanoma	Occasional (5-29%)
HP:0012758	Neurodevelopmental delay	Occasional (5-29%)
HP:0000028	Cryptorchidism	Very rare (<1-4%)
HP:0004912	Hypophosphatemic rickets	Very rare (<1-4%)
HP:0010314	Premature thelarche	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	large congenital melanocytic nevus
Mondo ID	MONDO:0044792
OMIM	137550
Orphanet	626
DOID	DOID:0111359
ICD-11	618273329
NCIT	C3944, C4234
SNOMED CT	254815002, 398696001
UMLS	C1842036
MedGen	330752
GARD	0002469
MedDRA	10072036
NORD	1184
Is cancer (heuristic)	no

Also known as: bathing trunk nevus · CMNS · congenital giant pigmented nevus · congenital hairy nevus · congenital melanocytic nevi · congenital melanocytic nevus · congenital melanocytic nevus of skin · congenital melanocytic nevus of the skin · congenital nevus · congenital nevus of skin · congenital nevus of the skin · congenital pigmented melanocytic Nevus · congenital pigmented nevus of skin · congenital pigmented nevus of the skin · congenital pigmented skin nevus · congenital skin nevus · Giant Congenital Melanocytic Nevus · giant congenital melanocytic nevus · giant congenital nevus · giant hairy nevus (+8 more)

Data availability: 29 ClinVar variants · 1 GenCC gene-disease record · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › integumentary system benign neoplasm › benign neoplasm of skin › melanocytic nevus › large congenital melanocytic nevus

Related subtypes (27): conjunctival nevus, blue nevus, halo nevus, intradermal nevus, pigmented spindle cell nevus, nevus, epidermal, neurocutaneous melanocytosis, neutrophil actin dysfunction, CHILD syndrome, Becker nevus syndrome, CLOVES syndrome, nevus comedonicus syndrome, segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome, congenital panfollicular nevus, porokeratotic eccrine ostial and dermal duct nevus, hereditary mucosal leukokeratosis, linear verrucous nevus syndrome, nevus of Ota, nevus of Ito, phakomatosis pigmentokeratotica, PENS syndrome, Angora hair nevus, didymosis aplasticosebacea, scalp syndrome, Nevada syndrome, palpebral nevus, benign melanocytic skin nevus

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

29 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 6 pathogenic, 3 benign, 2 likely pathogenic, 2 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign/likely 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
391700	NM_005343.4(HRAS):c.179G>T (p.Gly60Val)	HRAS	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
39648	NM_002524.5(NRAS):c.35G>A (p.Gly12Asp)	NRAS	Pathogenic/Likely 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
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
73058	NM_002524.5(NRAS):c.181C>A (p.Gln61Lys)	NRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
267819	46;X;inv(X)(q26q28)dn		Uncertain significance	criteria provided, single submitter
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
45304	NM_005343.4(HRAS):c.412G>A (p.Gly138Ser)	HRAS	Uncertain significance	reviewed by expert panel
503537	NM_005343.4(HRAS):c.11A>G (p.Tyr4Cys)	HRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
644041	NM_005343.4(HRAS):c.481C>T (p.Arg161Cys)	HRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
835903	NM_005343.4(HRAS):c.410A>C (p.Tyr137Ser)	HRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
850426	NM_005343.4(HRAS):c.491G>C (p.Arg164Pro)	HRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
477662	NM_002524.5(NRAS):c.25G>A (p.Val9Ile)	NRAS	Uncertain significance	criteria provided, multiple submitters, no conflicts
40448	NM_005343.4(HRAS):c.520C>T (p.Pro174Ser)	HRAS	Benign	reviewed by expert panel
448926	NM_005343.4(HRAS):c.291-6T>G	HRAS	Benign	reviewed by expert panel
45300	NM_005343.4(HRAS):c.330C>T (p.Pro110=)	HRAS	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
40441	NM_005343.4(HRAS):c.357C>T (p.Asp119=)	LRRC56	Benign	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · 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
BRAF	Strong	Autosomal dominant	large congenital melanocytic nevus	23

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease
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
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	gencc
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)
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
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
Kinase	1	6.9×	0.410
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
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
buccal mucosa cell	1
calcaneal tendon	1
colonic epithelium	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
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
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: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HRAS	8,064
NRAS	7,598
BRAF	7,394
LRRC56	914

Intra-cohort edges

A	B	Sources
BRAF	HRAS	intact, string_interaction
BRAF	NRAS	biogrid_interaction, intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HRAS	P01112	246
BRAF	P15056	131
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: 98. 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
RAF activation	3	335.9×	7e-07	BRAF, HRAS, NRAS
Signaling by high-kinase activity BRAF mutants	3	317.2×	7e-07	BRAF, HRAS, NRAS
MAP2K and MAPK activation	3	285.5×	7e-07	BRAF, HRAS, NRAS
Signaling by RAF1 mutants	3	278.5×	7e-07	BRAF, HRAS, NRAS
Negative regulation of MAPK pathway	3	265.6×	7e-07	BRAF, HRAS, NRAS
Signaling by moderate kinase activity BRAF mutants	3	253.8×	7e-07	BRAF, HRAS, NRAS
Paradoxical activation of RAF signaling by kinase inactive BRAF	3	253.8×	7e-07	BRAF, HRAS, NRAS
Signaling downstream of RAS mutants	3	253.8×	7e-07	BRAF, HRAS, NRAS
Signaling by RAS GAP mutants	2	2537.8×	1e-06	HRAS, NRAS
Signaling by RAS GTPase mutants	2	2537.8×	1e-06	HRAS, NRAS
Signaling by BRAF and RAF1 fusions	3	170.4×	2e-06	BRAF, HRAS, NRAS
Activation of RAS in B cells	2	1522.7×	4e-06	HRAS, NRAS
RAS signaling downstream of NF1 loss-of-function variants	2	1087.6×	7e-06	HRAS, NRAS
Estrogen-stimulated signaling through PRKCZ	2	1087.6×	7e-06	HRAS, NRAS
SOS-mediated signalling	2	951.7×	8e-06	HRAS, NRAS
Activated NTRK3 signals through RAS	2	845.9×	1e-05	HRAS, NRAS
EGFR Transactivation by Gastrin	2	761.3×	1e-05	HRAS, NRAS
SHC-related events triggered by IGF1R	2	761.3×	1e-05	HRAS, NRAS
Activated NTRK2 signals through RAS	2	761.3×	1e-05	HRAS, NRAS
MET activates RAS signaling	2	692.1×	1e-05	HRAS, NRAS
Signaling by FGFR4 in disease	2	634.4×	1e-05	HRAS, NRAS
Activated NTRK2 signals through FRS2 and FRS3	2	634.4×	1e-05	HRAS, NRAS
Constitutive Signaling by Overexpressed ERBB2	2	634.4×	1e-05	HRAS, NRAS
p38MAPK events	2	585.6×	1e-05	HRAS, NRAS
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	2	585.6×	1e-05	HRAS, NRAS
Signaling by PDGFRA extracellular domain mutants	2	585.6×	1e-05	HRAS, NRAS
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	2	543.8×	2e-05	HRAS, NRAS
RAF/MAP kinase cascade	3	61.1×	2e-05	BRAF, HRAS, NRAS
GRB2 events in EGFR signaling	2	507.6×	2e-05	HRAS, NRAS
Erythropoietin activates RAS	2	507.6×	2e-05	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
MAPK cascade	3	114.9×	8e-05	BRAF, HRAS, NRAS
Ras protein signal transduction	2	102.8×	0.004	HRAS, NRAS
animal organ morphogenesis	2	95.8×	0.004	BRAF, HRAS
T cell receptor signaling pathway	2	75.9×	0.005	BRAF, HRAS
regulation of cell population proliferation	2	57.7×	0.006	BRAF, HRAS
negative regulation of neuron apoptotic process	2	55.4×	0.006	BRAF, HRAS
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	1404.3×	0.007	BRAF
positive regulation of miRNA metabolic process	1	1404.3×	0.007	HRAS
positive regulation of ERK1 and ERK2 cascade	2	42.6×	0.007	BRAF, HRAS
positive regulation of axon regeneration	1	842.6×	0.008	BRAF
negative regulation of synaptic vesicle exocytosis	1	842.6×	0.008	BRAF
CD4-positive, alpha-beta T cell differentiation	1	702.2×	0.009	BRAF
myeloid progenitor cell differentiation	1	601.9×	0.009	BRAF
oncogene-induced cell senescence	1	601.9×	0.009	HRAS
positive regulation of D-glucose transmembrane transport	1	526.6×	0.009	BRAF
head morphogenesis	1	526.6×	0.009	BRAF
T-helper 1 type immune response	1	468.1×	0.009	HRAS
establishment of protein localization to membrane	1	468.1×	0.009	BRAF
negative regulation of fibroblast migration	1	383.0×	0.011	BRAF
endothelial cell apoptotic process	1	324.1×	0.012	BRAF
regulation of T cell differentiation	1	300.9×	0.012	BRAF
Schwann cell development	1	263.3×	0.013	HRAS
regulation of long-term neuronal synaptic plasticity	1	247.8×	0.013	HRAS
positive regulation of ruffle assembly	1	247.8×	0.013	HRAS
regulation of neurotransmitter receptor localization to postsynaptic specialization membrane	1	221.7×	0.014	HRAS
face development	1	200.6×	0.014	BRAF
synaptic vesicle exocytosis	1	191.5×	0.014	BRAF
positive regulation of peptidyl-serine phosphorylation	1	191.5×	0.014	BRAF
stress fiber assembly	1	191.5×	0.014	BRAF
postsynaptic modulation of chemical synaptic transmission	1	168.5×	0.015	BRAF

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
BRAF	VEMURAFENIB
HRAS	LONAFARNIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRAF	48	4
HRAS	4	4
NRAS	1	1
LRRC56	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
LONAFARNIB	4	HRAS
MASITINIB	3	BRAF
AVUTOMETINIB	3	BRAF
NAPORAFENIB	3	BRAF
QUERCETIN	3	BRAF
MOTESANIB	3	BRAF
DORAMAPIMOD	2	BRAF
FORETINIB	2	BRAF
REBASTINIB	2	BRAF
CEP-32496	2	BRAF

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
HRAS	48	Binding:45, Functional:3
NRAS	18	Binding:18

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
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
BRAF	1,442

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

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)
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
LONAFARNIB	4	HRAS
MASITINIB	3	BRAF
AVUTOMETINIB	3	BRAF
NAPORAFENIB	3	BRAF
QUERCETIN	3	BRAF
MOTESANIB	3	BRAF
DORAMAPIMOD	2	BRAF
FORETINIB	2	BRAF
REBASTINIB	2	BRAF
CEP-32496	2	BRAF

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	BRAF, 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: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04999631	EARLY_PHASE1	NOT_YET_RECRUITING	SADBE for Congenital Melanocytic Nevi
NCT06605417	Not specified	RECRUITING	Understanding the Transition from Normal Melanocytes to Nevus to Melanoma
NCT06605443	Not specified	RECRUITING	Precision Medicine for L/GCMN and Melanoma 2
NCT06828822	Not specified	RECRUITING	CongenItal Naevus Cohort for Longitudinal Evaluation
NCT06934759	Not specified	ENROLLING_BY_INVITATION	Impact and Lived Experience of Parents of a Child With a Large or Giant Congenital Melanocytic Nevus

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ALCOHOL	4	1
SQUARIC ACID DIBUTYL ESTER	2	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 1 predictive associations from 1 curated evidence items.

Molecular subtype	Therapy	Effect	Level	CIViC
AKAP9::BRAF Fusion	Trametinib	Sensitivity/Response	CIViC C	EID7759