Dowling-Degos disease 1

Summary

Dowling-Degos disease 1 (MONDO:0024534) is a disease caused by KRT5 (GenCC Strong), with 1 cohort gene and 7 clinical trials. Top therapeutic interventions include pegcetacoplan.

At a glance

• Causal gene: KRT5 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 14
• Clinical trials: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Dowling-Degos disease 1
Mondo ID	MONDO:0024534
OMIM	179850
UMLS	C4552092
MedGen	1645697
GARD	0025416
Is cancer (heuristic)	no

Also known as: DDD · DDD1 · Dowling-Degos disease 1 · Dowling-Degos disease caused by mutation in KRT5 · KRT5 Dowling-Degos disease

Data availability: 14 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › skin pigmentation disorder › reticulate pigment disorder › Dowling-Degos disease › Dowling-Degos disease 1

Related subtypes (3): Dowling-Degos disease 2, dowling-degos disease 3, Dowling-Degos disease 4

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

14 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
14641	NM_000424.4(KRT5):c.980T>C (p.Met327Thr)	KRT5	Pathogenic	criteria provided, multiple submitters, no conflicts
14647	NM_000424.4(KRT5):c.14C>A (p.Ser5Ter)	KRT5	Pathogenic	no assertion criteria provided
2137373	NM_000424.4(KRT5):c.597G>C (p.Lys199Asn)	KRT5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66235	NM_000424.4(KRT5):c.418dup (p.Ile140fs)	KRT5	Pathogenic	criteria provided, single submitter
66298	NM_000424.4(KRT5):c.991C>T (p.Arg331Cys)	KRT5	Pathogenic	criteria provided, multiple submitters, no conflicts
3891530	NM_000424.4(KRT5):c.1219_1229del (p.Cys407fs)	KRT5	Likely pathogenic	criteria provided, single submitter
3891531	NM_000424.4(KRT5):c.1219-20_1229del	KRT5	Likely pathogenic	criteria provided, single submitter
3382368	NM_000424.4(KRT5):c.1434A>C (p.Glu478Asp)	KRT5	Uncertain significance	criteria provided, single submitter
3536083	NM_000424.4(KRT5):c.650C>T (p.Pro217Leu)	KRT5	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891528	NM_000424.4(KRT5):c.1054C>T (p.Arg352Cys)	KRT5	Uncertain significance	criteria provided, single submitter
3891529	NM_000424.4(KRT5):c.643C>A (p.Leu215Met)	KRT5	Uncertain significance	criteria provided, single submitter
982659	NM_000424.4(KRT5):c.224C>A (p.Ser75Tyr)	KRT5	Uncertain significance	criteria provided, multiple submitters, no conflicts
309575	NM_000424.4(KRT5):c.110G>A (p.Arg37Gln)	KRT5	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
66277	NM_000424.4(KRT5):c.594C>A (p.Thr198=)	KRT5	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 6 · 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
KRT5	Definitive	Autosomal dominant	Dowling-Degos disease	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRT5	Orphanet:158681	Epidermolysis bullosa simplex with circinate migratory erythema
KRT5	Orphanet:79145	Dowling-Degos disease
KRT5	Orphanet:79396	Autosomal dominant generalized epidermolysis bullosa simplex, severe form
KRT5	Orphanet:79397	Epidermolysis bullosa simplex with mottled pigmentation
KRT5	Orphanet:79399	Autosomal dominant generalized epidermolysis bullosa simplex, intermediate form
KRT5	Orphanet:79400	Localized epidermolysis bullosa simplex

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
KRT5	HGNC:6442	ENSG00000186081	P13647	Keratin, type II cytoskeletal 5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRT5	Keratin, type II cytoskeletal 5	Required for the formation of keratin intermediate filaments in the basal epidermis and maintenance of the skin barrier in response to mechanical stress.

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)
KRT5	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head

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
gingiva	1
lower esophagus mucosa	1
pharyngeal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT5	211	broad	marker	lower esophagus mucosa, pharyngeal mucosa, gingiva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT5	3,406

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRT5	P13647	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Type I hemidesmosome assembly	1	1038.2×	0.006	KRT5
Developmental Lineage of Mammary Stem Cells	1	761.3×	0.006	KRT5
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	543.8×	0.006	KRT5
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	456.8×	0.006	KRT5
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	278.5×	0.008	KRT5
Developmental Cell Lineages	1	223.9×	0.008	KRT5
Cell junction organization	1	187.2×	0.008	KRT5
Cell-Cell communication	1	137.6×	0.010	KRT5
Formation of the cornified envelope	1	87.8×	0.014	KRT5
Keratinization	1	55.7×	0.020	KRT5
Developmental Biology	1	14.5×	0.069	KRT5

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
intermediate filament polymerization	1	16852.0×	4e-04	KRT5
response to mechanical stimulus	1	300.9×	0.006	KRT5
intermediate filament organization	1	240.7×	0.006	KRT5
keratinization	1	234.1×	0.006	KRT5
epidermis development	1	210.7×	0.006	KRT5
regulation of protein localization	1	205.5×	0.006	KRT5
regulation of cell migration	1	157.5×	0.006	KRT5

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KRT5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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).

Chemical tractability of cohort targets

0 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.

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	KRT5

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)
KRT5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE3	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05809531	PHASE3	ACTIVE_NOT_RECRUITING	An Open-Label, Nonrandomized, Multicenter Extension Study to Evaluate the Long-term Safety and Efficacy of Pegcetacoplan in Participants With C3 Glomerulopathy or Immune-Complex Membranoproliferative Glomerulonephritis
NCT05067127	PHASE3	COMPLETED	Phase III Study Assessing the Efficacy and Safety of Pegcetacoplan in Patients With C3 Glomerulopathy or Immune-Complex Membranoproliferative Glomerulonephritis
NCT07386548	Not specified	NOT_YET_RECRUITING	Biologic Injection For Adults With Lumbar Disc Herniation
NCT01343693	Not specified	COMPLETED	MaxAn Post Market Surveillance Validation
NCT01796535	Not specified	UNKNOWN	The PerX360º System™ Registry
NCT04729062	Not specified	APPROVED_FOR_MARKETING	C3G/Primary IC-MPGN EAP
NCT04782011	Not specified	UNKNOWN	Using the ATC/DDD to Monitor Antibiotic Use at Lower Primary Care Facilities in Southwestern Uganda

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PEGCETACOPLAN	4	3