Melanoma, cutaneous malignant, susceptibility to, 3

Summary

Melanoma, cutaneous malignant, susceptibility to, 3 (MONDO:0012183) is a cancer caused by CDK4 (GenCC Definitive), with 3 cohort genes (1 CIViC-evidence somatic driver; 383 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Causal gene: CDK4 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 383

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	melanoma, cutaneous malignant, susceptibility to, 3
Mondo ID	MONDO:0012183
OMIM	609048
UMLS	C1836892
MedGen	373202
GARD	0027812
Is cancer (heuristic)	yes

Also known as: CMM3 · melanoma, cutaneous malignant, 3 · melanoma, cutaneous malignant, susceptibility to, 3 · melanoma, cutaneous malignant, susceptibility to, type 3

Data availability: 383 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › susceptibility to familial cutaneous melanoma › melanoma, cutaneous malignant, susceptibility to, 3

Related subtypes (9): melanoma, cutaneous malignant, susceptibility to, 1, melanoma, cutaneous malignant, susceptibility to, 2, melanoma, cutaneous malignant, susceptibility to, 4, melanoma, cutaneous malignant, susceptibility to, 7, melanoma, cutaneous malignant, susceptibility to, 5, melanoma, cutaneous malignant, susceptibility to, 6, melanoma, cutaneous malignant, susceptibility to, 8, melanoma, cutaneous malignant, susceptibility to, 9, tumor predisposition syndrome 3

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

383 retrieved; paginated sample, class counts are floors:

177 benign/likely benign, 71 likely benign, 52 benign, 42 conflicting classifications of pathogenicity, 39 uncertain significance, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16928	NM_000075.4(CDK4):c.70C>T (p.Arg24Cys)	CDK4	Pathogenic	criteria provided, multiple submitters, no conflicts
16929	NM_000075.4(CDK4):c.71G>A (p.Arg24His)	CDK4	Pathogenic	criteria provided, multiple submitters, no conflicts
1006266	NM_000075.4(CDK4):c.632+6G>A	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
133874	NM_000075.4(CDK4):c.364C>T (p.Arg122Cys)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
133876	NM_000075.4(CDK4):c.661G>A (p.Asp221Asn)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
133877	NM_000075.4(CDK4):c.763C>T (p.Arg255Cys)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
135825	NM_000075.4(CDK4):c.625C>T (p.Arg209Cys)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1522817	NM_000075.4(CDK4):c.354+3G>A	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1623120	NM_000075.4(CDK4):c.780G>A (p.Val260=)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1753311	NM_000075.4(CDK4):c.63C>T (p.Tyr21=)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1762534	NM_000075.4(CDK4):c.822A>G (p.Glu274=)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
184333	NM_000075.4(CDK4):c.764G>A (p.Arg255His)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
186740	NM_000075.4(CDK4):c.42C>T (p.Val14=)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309978	NM_000075.4(CDK4):c.747T>C (p.Phe249=)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309980	NM_000075.4(CDK4):c.267A>G (p.Val89=)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309985	NM_000075.4(CDK4):c.-123T>G	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3230238	NM_000075.4(CDK4):c.570A>G (p.Thr190=)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3378439	NM_000075.4(CDK4):c.171G>A (p.Val57=)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3378684	NM_000075.4(CDK4):c.669G>A (p.Leu223=)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
419527	NM_000075.4(CDK4):c.14G>A (p.Arg5Gln)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
439047	NM_000075.4(CDK4):c.632+5dup	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
463475	NM_000075.4(CDK4):c.632+9C>T	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
483281	NM_000075.4(CDK4):c.279T>C (p.Phe93=)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
483307	NM_000075.4(CDK4):c.263A>G (p.Lys88Arg)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
483317	NM_000075.4(CDK4):c.219-5G>C	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
510755	NM_000075.4(CDK4):c.683+8A>T	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
581775	NM_000075.4(CDK4):c.48C>G (p.Ala16=)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
697484	NM_000075.4(CDK4):c.354+9G>C	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
824901	NM_000075.4(CDK4):c.444G>T (p.Val148=)	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
826324	NM_000075.4(CDK4):c.632+4T>A	CDK4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
CDK4	LoF	MEL	CIViC #13

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
CDK4	Definitive	Autosomal dominant	melanoma, cutaneous malignant, susceptibility to, 3	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CDK4	Orphanet:618	Familial melanoma
CDK4	Orphanet:99970	Dedifferentiated liposarcoma
CDK4	Orphanet:99971	Well-differentiated liposarcoma

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CDK4	HGNC:1773	ENSG00000135446	P11802	Cyclin-dependent kinase 4	gencc,clinvar
TSPAN31	HGNC:10539	ENSG00000135452	Q12999	Tetraspanin-31	clinvar
MIR6759	HGNC:50063	ENSG00000283621		microRNA 6759	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDK4	Cyclin-dependent kinase 4	Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S transition.

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
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CDK4	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
TSPAN31	Other/Unknown	no		Tetraspanin_animals, Tetraspanin/Peripherin
MIR6759	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 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)	1
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
embryo	1
ganglionic eminence	1
ventricular zone	1
islet of Langerhans	1
pancreatic ductal cell	1
pericardium	1
colon	1
gastrocnemius	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDK4	138	ubiquitous	marker	embryo, ganglionic eminence, ventricular zone
TSPAN31	288	ubiquitous	marker	pancreatic ductal cell, islet of Langerhans, pericardium
MIR6759	11		yes	colon, right atrium auricular region, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDK4	8,412
TSPAN31	593
MIR6759	0

Intra-cohort edges

A	B	Sources
CDK4	TSPAN31	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDK4	P11802	15

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TSPAN31	Q12999	89.29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 50. Enrichment computed across 3 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4	1	5710.0×	0.002	CDK4
Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4	1	5710.0×	0.002	CDK4
Diseases of Cellular Senescence	1	3806.7×	0.002	CDK4
Evasion of Oncogene Induced Senescence Due to p16INK4A Defects	1	3806.7×	0.002	CDK4
Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6	1	3806.7×	0.002	CDK4
Evasion of Oxidative Stress Induced Senescence Due to p16INK4A Defects	1	3806.7×	0.002	CDK4
Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6	1	3806.7×	0.002	CDK4
Diseases of cellular response to stress	1	3806.7×	0.002	CDK4
Drug-mediated inhibition of CDK4/CDK6 activity	1	2284.0×	0.002	CDK4
PTK6 Regulates Cell Cycle	1	1903.3×	0.003	CDK4
Aberrant regulation of mitotic G1/S transition in cancer due to RB1 defects	1	878.5×	0.005	CDK4
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)	1	634.4×	0.007	CDK4
Signaling by PTK6	1	543.8×	0.007	CDK4
Signaling by Non-Receptor Tyrosine Kinases	1	543.8×	0.007	CDK4
Aberrant regulation of mitotic cell cycle due to RB1 defects	1	407.9×	0.007	CDK4
G1 Phase	1	393.8×	0.007	CDK4
Diseases of mitotic cell cycle	1	393.8×	0.007	CDK4
Oncogene Induced Senescence	1	335.9×	0.008	CDK4
Meiosis	1	285.5×	0.008	CDK4
Cyclin E associated events during G1/S transition	1	285.5×	0.008	CDK4
Cyclin A:Cdk2-associated events at S phase entry	1	265.6×	0.008	CDK4
Ubiquitin-dependent degradation of Cyclin D	1	265.6×	0.008	CDK4
Transcriptional regulation by RUNX2	1	253.8×	0.008	CDK4
G1/S Transition	1	233.1×	0.008	CDK4
Cyclin D associated events in G1	1	233.1×	0.008	CDK4
SPOP-mediated proteasomal degradation of PD-L1(CD274)	1	228.4×	0.008	CDK4
SCF(Skp2)-mediated degradation of p27/p21	1	207.6×	0.009	CDK4
Reproduction	1	190.3×	0.009	CDK4
Mitotic G1 phase and G1/S transition	1	184.2×	0.009	CDK4
S Phase	1	181.3×	0.009	CDK4

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of transcription initiation by RNA polymerase II	1	2808.7×	0.004	CDK4
cellular response to ionomycin	1	1404.3×	0.004	CDK4
regulation of type B pancreatic cell proliferation	1	1053.2×	0.004	CDK4
positive regulation of cell population proliferation	2	33.6×	0.004	CDK4, TSPAN31
regulation of G2/M transition of mitotic cell cycle	1	648.1×	0.004	CDK4
cellular response to phorbol 13-acetate 12-myristate	1	648.1×	0.004	CDK4
cellular response to interleukin-4	1	324.1×	0.007	CDK4
positive regulation of G2/M transition of mitotic cell cycle	1	300.9×	0.007	CDK4
positive regulation of fibroblast proliferation	1	147.8×	0.012	CDK4
G1/S transition of mitotic cell cycle	1	100.3×	0.016	CDK4
cellular response to lipopolysaccharide	1	49.0×	0.030	CDK4
regulation of gene expression	1	41.7×	0.032	CDK4
regulation of cell cycle	1	37.3×	0.033	CDK4
response to xenobiotic stimulus	1	34.5×	0.033	CDK4
cell division	1	23.1×	0.046	CDK4
signal transduction	1	8.0×	0.121	CDK4

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
CDK4	PALBOCICLIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDK4	56	4
TSPAN31	0	0
MIR6759	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PALBOCICLIB	4	CDK4
ABEMACICLIB	4	CDK4
RIBOCICLIB	4	CDK4
TRILACICLIB	4	CDK4
FEDRATINIB	4	CDK4
DABRAFENIB	4	CDK4
CERITINIB	4	CDK4
ENCORAFENIB	4	CDK4
GILTERITINIB	4	CDK4
NINTEDANIB	4	CDK4
SUNITINIB	4	CDK4
DINACICLIB	3	CDK4
LEROCICLIB	3	CDK4
ALVOCIDIB	3	CDK4
QUERCETIN	3	CDK4
DALPICICLIB	3	CDK4
DOVITINIB	3	CDK4
LESTAURTINIB	3	CDK4
RUBOXISTAURIN	3	CDK4
INDIRUBIN	2	CDK4
SELICICLIB	2	CDK4
REBASTINIB	2	CDK4
NARAZACICLIB	2	CDK4
RIVICICLIB	2	CDK4
RG-547	2	CDK4
VORUCICLIB	2	CDK4
ULECACICLIB	2	CDK4
CROZBACICLIB	2	CDK4
RONICICLIB	2	CDK4
EBVACICLIB	2	CDK4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CDK4	1,142	Binding:1086, Functional:53, ADMET:2, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CDK4	2.7.11.22	cyclin-dependent kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CDK4	1,142

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

30 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Compound	Max phase	Cohort target (bioactivity)
PALBOCICLIB	4	CDK4
ABEMACICLIB	4	CDK4
RIBOCICLIB	4	CDK4
TRILACICLIB	4	CDK4
FEDRATINIB	4	CDK4
DABRAFENIB	4	CDK4
CERITINIB	4	CDK4
ENCORAFENIB	4	CDK4
GILTERITINIB	4	CDK4
NINTEDANIB	4	CDK4
SUNITINIB	4	CDK4
DINACICLIB	3	CDK4
LEROCICLIB	3	CDK4
ALVOCIDIB	3	CDK4
QUERCETIN	3	CDK4
DALPICICLIB	3	CDK4
DOVITINIB	3	CDK4
LESTAURTINIB	3	CDK4
RUBOXISTAURIN	3	CDK4
INDIRUBIN	2	CDK4
SELICICLIB	2	CDK4
REBASTINIB	2	CDK4
NARAZACICLIB	2	CDK4
RIVICICLIB	2	CDK4
RG-547	2	CDK4
VORUCICLIB	2	CDK4
ULECACICLIB	2	CDK4
CROZBACICLIB	2	CDK4
RONICICLIB	2	CDK4
EBVACICLIB	2	CDK4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CDK4
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	TSPAN31, MIR6759

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)
TSPAN31	0	—
MIR6759	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.