epidermolysis bullosa simplex 2A, generalized severe

Summary

epidermolysis bullosa simplex 2A, generalized severe (MONDO:0030489) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	epidermolysis bullosa simplex 2A, generalized severe
Mondo ID	MONDO:0030489
OMIM	619555
GARD	0025580
Is cancer (heuristic)	no

Also known as: EBS2A

Data availability: 15 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › vesiculobullous skin disease › epidermolysis bullosa › inherited epidermolysis bullosa › epidermolysis bullosa simplex › epidermolysis bullosa simplex 2A, generalized severe

Related subtypes (19): epidermolysis bullosa simplex 1A, generalized severe, epidermolysis bullosa simplex 1C, localized, epidermolysis bullosa simplex 1B, generalized intermediate, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 2F, with mottled pigmentation, epidermolysis bullosa simplex 5B, with muscular dystrophy, epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive, epidermolysis bullosa simplex 7, with nephropathy and deafness, epidermolysis bullosa simplex 2E, with migratory circinate erythema, epidermolysis bullosa simplex 5C, with pyloric atresia, epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive, epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency, epidermolysis bullosa simplex with nail dystrophy, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, suprabasal epidermolysis bullosa simplex, epidermolysis bullosa simplex with anodontia/hypodontia, epidermolysis bullosa simplex 2B, generalized intermediate, epidermolysis bullosa simplex 2C, localized, epidermolysis bullosa simplex 2d, generalized, intermediate or severe, autosomal recessive

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

15 retrieved; paginated sample, class counts are floors:

5 pathogenic, 4 uncertain significance, 2 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
14638	NM_000424.4(KRT5):c.1424A>G (p.Glu475Gly)	KRT5	Pathogenic	no assertion criteria provided
14645	NM_000424.4(KRT5):c.523C>T (p.Leu175Phe)	KRT5	Pathogenic	no assertion criteria provided
14653	NM_000424.4(KRT5):c.1429G>T (p.Glu477Ter)	KRT5	Pathogenic	no assertion criteria provided
21174	NM_000424.4(KRT5):c.1429G>A (p.Glu477Lys)	KRT5	Pathogenic	criteria provided, multiple submitters, no conflicts
265218	NM_000424.4(KRT5):c.555+1G>A	KRT5	Pathogenic	criteria provided, single submitter
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
2765862	NM_000424.4(KRT5):c.1398G>T (p.Glu466Asp)	KRT5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
66213	NM_000424.4(KRT5):c.1411C>T (p.Arg471Cys)	KRT5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
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
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: 0 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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	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: 0.