Melanoma, uveal, susceptibility to, 1

Summary

Melanoma, uveal, susceptibility to, 1 (MONDO:0011695) is a cancer with 1 cohort gene (1 CIViC-evidence somatic driver; 10 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Cohort genes: 1
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	melanoma, uveal, susceptibility to, 1
Mondo ID	MONDO:0011695
OMIM	606660
UMLS	C1847724
MedGen	376198
GARD	0027802
Is cancer (heuristic)	yes

Also known as: melanoma, uveal, susceptibility to, 1 · melanoma, uveal, susceptibility to, type 1 · UVM1

Data availability: 10 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › susceptibility to uveal melanoma › melanoma, uveal, susceptibility to, 1

Related subtypes (1): melanoma, uveal, susceptibility to, 2

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

10 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 3 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1338644	NM_001276270.2(MBD4):c.939dup (p.Glu314fs)	MBD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700251	NM_001276270.2(MBD4):c.1544-1G>T	MBD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700254	NM_001276270.2(MBD4):c.1670T>A (p.Leu557Ter)	MBD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1879591	NM_001276270.2(MBD4):c.572C>T (p.Pro191Leu)	MBD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3543746	NM_001276270.2(MBD4):c.76C>G (p.Leu26Val)	MBD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1338066	NM_001276270.2(MBD4):c.1160C>T (p.Ser387Leu)	MBD4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1700256	NM_001276270.2(MBD4):c.1688G>A (p.Trp563Ter)	MBD4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1700257	NM_001276270.2(MBD4):c.1384C>T (p.Arg462Trp)	MBD4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2712037	NM_001276270.2(MBD4):c.1636G>A (p.Glu546Lys)	MBD4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3543756	NM_001276270.2(MBD4):c.229A>G (p.Thr77Ala)	MBD4	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
MBD4			CIViC #7084

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
MBD4	Limited	Autosomal dominant	melanoma, uveal, susceptibility to, 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MBD4	Orphanet:661526	MBD4-related tumor predisposition syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MBD4	HGNC:6919	ENSG00000129071	O95243	Methyl-CpG-binding domain protein 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MBD4	Methyl-CpG-binding domain protein 4	Mismatch-specific DNA N-glycosylase involved in DNA repair.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MBD4	Other/Unknown	no		Methyl_CpG_DNA-bd, DNA_glycosylase, DNA-bd_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
pylorus	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MBD4	299	ubiquitous	marker	secondary oocyte, oocyte, pylorus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MBD4	1,362

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MBD4	O95243	18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 1 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
Resolution of Abasic Sites (AP sites)	1	1142.0×	0.002	MBD4
Displacement of DNA glycosylase by APEX1	1	1038.2×	0.002	MBD4
Depyrimidination	1	951.7×	0.002	MBD4
Base-Excision Repair, AP Site Formation	1	878.5×	0.002	MBD4
Base Excision Repair	1	713.8×	0.002	MBD4
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	184.2×	0.006	MBD4
Cleavage of the damaged pyrimidine	1	184.2×	0.006	MBD4
DNA Repair	1	98.5×	0.010	MBD4

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
depyrimidination	1	1872.4×	0.002	MBD4
response to estradiol	1	198.3×	0.008	MBD4
DNA repair	1	63.8×	0.016	MBD4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MBD4	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
MBD4	1	Functional:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

0 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.

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	0
E	Difficult family or no structure, no drug	1	MBD4

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)
MBD4	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.