Hyperpigmentation of the skin

Summary

Hyperpigmentation of the skin (MONDO:0019289) is a disease (an umbrella term covering 24 Mondo subtypes) with 3 cohort genes.

At a glance

• Umbrella term: 24 Mondo subtypes
• Cohort genes: 3
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperpigmentation of the skin
Mondo ID	MONDO:0019289
Orphanet	79375
SNOMED CT	49765009
UMLS	C0162834
MedGen	57992
Is cancer (heuristic)	no

Data availability: 8 ClinVar variants · 1 HPO phenotype.

Disease family

An umbrella term covering 24 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › skin pigmentation disorder › hyperpigmentation of the skin

Related subtypes (3): reticulate pigment disorder, hypo- and hypermelanotic cutaneous macules-retarded growth-intellectual disability syndrome, hypopigmentation of the skin

Subtypes (24): dyschromatosis universalis hereditaria, cafe au lait spots, multiple, dermatopathia pigmentosa reticularis, dyschromatosis symmetrica hereditaria, extrasystoles-short stature-hyperpigmentation-microcephaly syndrome, gastrocutaneous syndrome, hyperkeratosis-hyperpigmentation syndrome, familial generalized lentiginosis, Naegeli-Franceschetti-Jadassohn syndrome, schwannomatosis, Dowling-Degos disease, H syndrome, Legius syndrome, familial progressive hyperpigmentation, linear and whorled nevoid hypermelanosis, reticulate acropigmentation of Kitamura, nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome, severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome, leukonychia totalis-acanthosis-nigricans-like lesions-abnormal hair syndrome, osteopathia striata-pigmentary dermopathy-white forelock syndrome, phakomatosis pigmentovascularis, acromelanosis, hyperpigmentation, progressive cribriform and zosteriform, mosaic Legius syndrome

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

8 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 2 pathogenic, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17462	NM_000094.4(COL7A1):c.706C>T (p.Arg236Ter)	COL7A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17463	NM_000094.4(COL7A1):c.6205C>T (p.Arg2069Cys)	COL7A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2276	NM_014874.4(MFN2):c.280C>T (p.Arg94Trp)	MFN2	Pathogenic	criteria provided, multiple submitters, no conflicts
3767295	NM_001039591.3(USP9X):c.5719_5720del (p.Glu1907fs)	USP9X	Likely pathogenic	criteria provided, single submitter
267819	46;X;inv(X)(q26q28)dn		Uncertain significance	criteria provided, single submitter
267831	46;Y;inv(X)(q27q28)		Uncertain significance	criteria provided, single submitter
267835	46;XX;der(6)t(6;13)(q23.3;q22)inv(6)(p21.3q15);der(13)t(6;13)dn		Uncertain significance	criteria provided, single submitter
1683772	NM_000243.3(MEFV):c.1724C>G (p.Ser575Ter)	LOC126862264	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 16 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
USP9X	Orphanet:480880	X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability
USP9X	Orphanet:777	X-linked non-syndromic intellectual disability
MFN2	Orphanet:2398	Multiple symmetric lipomatosis
MFN2	Orphanet:64751	Hereditary motor and sensory neuropathy type 5
MFN2	Orphanet:90118	Severe early-onset axonal neuropathy due to MFN2 deficiency
MFN2	Orphanet:90120	Hereditary motor and sensory neuropathy type 6
MFN2	Orphanet:99947	Autosomal dominant Charcot-Marie-Tooth disease type 2A2
COL7A1	Orphanet:158673	Localized dystrophic epidermolysis bullosa, acral form
COL7A1	Orphanet:158676	Localized dystrophic epidermolysis bullosa, nails only
COL7A1	Orphanet:231568	Autosomal dominant generalized dystrophic epidermolysis bullosa
COL7A1	Orphanet:79408	Autosomal recessive generalized dystrophic epidermolysis bullosa, severe form
COL7A1	Orphanet:79409	Recessive dystrophic epidermolysis bullosa inversa
COL7A1	Orphanet:79410	Localized dystrophic epidermolysis bullosa, pretibial form
COL7A1	Orphanet:79411	Self-improving dystrophic epidermolysis bullosa
COL7A1	Orphanet:89842	Autosomal recessive generalized dystrophic epidermolysis bullosa, intermediate form
COL7A1	Orphanet:89843	Dystrophic epidermolysis bullosa pruriginosa

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
USP9X	HGNC:12632	ENSG00000124486	Q93008	Ubiquitin carboxyl-terminal hydrolase 9X	clinvar
MFN2	HGNC:16877	ENSG00000116688	O95140	Mitofusin-2	clinvar
COL7A1	HGNC:2214	ENSG00000114270	Q02388	Collagen alpha-1(VII) chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
USP9X	Ubiquitin carboxyl-terminal hydrolase 9X	Deubiquitinase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins.
MFN2	Mitofusin-2	Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion.
COL7A1	Collagen alpha-1(VII) chain	Stratified squamous epithelial basement membrane protein that forms anchoring fibrils which may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV c…

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Protease	1	12.2×	0.149
Antibody/Immunoglobulin	1	9.7×	0.149
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
USP9X	Protease	yes		Peptidase_C19_UCH, ARM-type_fold, USP_CS
MFN2	Other/Unknown	no		Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase
COL7A1	Antibody/Immunoglobulin	yes		VWF_A, Kunitz_BPTI, FN3_dom

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
endometrium epithelium	1
middle frontal gyrus	1
secondary oocyte	1
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
skin of abdomen	1
skin of leg	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
USP9X	295	ubiquitous	marker	middle frontal gyrus, endometrium epithelium, secondary oocyte
MFN2	297	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
COL7A1	267	ubiquitous	marker	stromal cell of endometrium, skin of abdomen, skin of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MFN2	3,853
USP9X	3,484
COL7A1	1,767

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
USP9X	Q93008	4
MFN2	O95140	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COL7A1	Q02388

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. Enrichment computed across 3 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
Miro GTPase Cycle	1	761.3×	0.023	MFN2
RHOT2 GTPase cycle	1	543.8×	0.023	MFN2
Mitophagy	1	346.1×	0.023	MFN2
Anchoring fibril formation	1	253.8×	0.023	COL7A1
Fibronectin matrix formation	1	190.3×	0.023	COL7A1
Laminin interactions	1	126.9×	0.023	COL7A1
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	122.8×	0.023	USP9X
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	1	122.8×	0.023	USP9X
PINK1-PRKN Mediated Mitophagy	1	119.0×	0.023	MFN2
Cargo concentration in the ER	1	112.0×	0.023	COL7A1
RHOV GTPase cycle	1	95.2×	0.023	USP9X
RHOU GTPase cycle	1	92.8×	0.023	USP9X
Selective autophagy	1	92.8×	0.023	MFN2
Collagen chain trimerization	1	86.5×	0.023	COL7A1
Assembly of collagen fibrils and other multimeric structures	1	66.8×	0.027	COL7A1
Collagen degradation	1	58.6×	0.027	COL7A1
Peroxisomal protein import	1	57.7×	0.027	USP9X
Collagen biosynthesis and modifying enzymes	1	56.8×	0.027	COL7A1
COPII-mediated vesicle transport	1	54.4×	0.027	COL7A1
Autophagy	1	49.4×	0.028	MFN2
Integrin cell surface interactions	1	44.8×	0.030	COL7A1
Macroautophagy	1	38.5×	0.033	MFN2
Amyloid fiber formation	1	34.3×	0.035	USP9X
Factors involved in megakaryocyte development and platelet production	1	22.1×	0.052	MFN2
Ub-specific processing proteases	1	17.7×	0.062	USP9X
Hemostasis	1	12.0×	0.087	MFN2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	11.2×	0.090	MFN2
Signal Transduction	1	3.4×	0.267	MFN2

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
type 2 mitophagy	1	1123.5×	0.009	MFN2
cytosolic ciliogenesis	1	1123.5×	0.009	USP9X
mitochondrial membrane organization	1	802.5×	0.009	MFN2
protein import into peroxisome matrix, receptor recycling	1	802.5×	0.009	USP9X
positive regulation of TORC2 signaling	1	702.2×	0.009	USP9X
positive regulation of vascular associated smooth muscle cell apoptotic process	1	702.2×	0.009	MFN2
positive regulation of protein binding	1	624.1×	0.009	USP9X
monoubiquitinated protein deubiquitination	1	624.1×	0.009	USP9X
mitochondrion localization	1	561.7×	0.009	MFN2
DNA alkylation repair	1	510.7×	0.009	USP9X
protein deubiquitination involved in ubiquitin-dependent protein catabolic process	1	432.1×	0.010	USP9X
protein localization to phagophore assembly site	1	330.4×	0.011	MFN2
mitochondrial fusion	1	280.9×	0.011	MFN2
female gamete generation	1	267.5×	0.011	USP9X
blastocyst formation	1	255.3×	0.011	MFN2
camera-type eye morphogenesis	1	255.3×	0.011	MFN2
negative regulation of Ras protein signal transduction	1	224.7×	0.011	MFN2
negative regulation of smooth muscle cell proliferation	1	208.1×	0.011	MFN2
protein K63-linked deubiquitination	1	208.1×	0.011	USP9X
amyloid fibril formation	1	200.6×	0.011	USP9X
obsolete protein targeting to mitochondrion	1	193.7×	0.011	MFN2
endodermal cell differentiation	1	165.2×	0.012	COL7A1
axon extension	1	165.2×	0.012	USP9X
positive regulation of vascular associated smooth muscle cell proliferation	1	144.0×	0.013	MFN2
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	133.8×	0.014	USP9X
response to unfolded protein	1	100.3×	0.018	MFN2
regulation of circadian rhythm	1	86.4×	0.019	USP9X
rhythmic process	1	83.8×	0.019	USP9X
aerobic respiration	1	82.6×	0.019	MFN2
epidermis development	1	70.2×	0.022	COL7A1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 3 of 3 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
USP9X	1	2
MFN2	0	0
COL7A1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ETAVOPIVAT	2	USP9X

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
USP9X	41	Binding:41
MFN2	3	Binding:3

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

1 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)
ETAVOPIVAT	2	USP9X

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	1	USP9X
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	COL7A1
E	Difficult family or no structure, no drug	1	MFN2

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)
MFN2	3	—
COL7A1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.