epidermolysis bullosa simplex 1B, generalized intermediate

Summary

epidermolysis bullosa simplex 1B, generalized intermediate (MONDO:0007554) is a disease caused by variants in KRT14 and KRT5, with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal genes: KRT14 (GenCC Strong), KRT5 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 26
• Phenotypes (HPO): 17

Clinical features

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0000962	Hyperkeratosis	Very frequent (80-99%)
HP:0003341	Junctional split	Very frequent (80-99%)
HP:0007585	Skin fragility with non-scarring blistering	Very frequent (80-99%)
HP:0008066	Abnormal blistering of the skin	Very frequent (80-99%)
HP:0005585	Spotty hyperpigmentation	Frequent (30-79%)
HP:0005590	Spotty hypopigmentation	Frequent (30-79%)
HP:0007556	Plantar hyperkeratosis	Frequent (30-79%)
HP:0010765	Palmar hyperkeratosis	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Occasional (5-29%)
HP:0001034	Hypermelanotic macule	Occasional (5-29%)
HP:0001056	Milia	Occasional (5-29%)
HP:0008404	Nail dystrophy	Occasional (5-29%)
HP:0009123	Mixed hypo- and hyperpigmentation of the skin	Occasional (5-29%)
HP:0009719	Hypomelanotic macule	Occasional (5-29%)
HP:0200097	Oral mucosal blisters	Occasional (5-29%)
HP:0000989	Pruritus	Very rare (<1-4%)
HP:0200034	Papule	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	epidermolysis bullosa simplex 1B, generalized intermediate
Mondo ID	MONDO:0007554
OMIM	131900
Orphanet	79399
DOID	DOID:0080511
SNOMED CT	90496008
UMLS	C5561924
MedGen	1794134
GARD	0002147
Is cancer (heuristic)	no

Also known as: EBS, generalised · EBS, generalised intermediate · EBS, generalized intermediate · EBS-K · epidermolysis bullosa simplex 1B, generalized intermediate · epidermolysis bullosa simplex, generalised · epidermolysis bullosa simplex, generalised intermediate · epidermolysis bullosa simplex, generalised non-Dowling-Meara · epidermolysis bullosa simplex, generalized non-Dowling-Meara · epidermolysis bullosa simplex, Kobner type · epidermolysis bullosa simplex, Koebner type · epidermolysis bullosa simplex, Köbner type · generalised EBS · generalised EBS, non-Dowling-Meara type · generalised epidermolysis bullosa simplex, non-Dowling-Meara type · generalized EBS · generalized EBS, non-Dowling-Meara type · generalized epidermolysis bullosa simplex, non-Dowling-Meara type

Data availability: 26 ClinVar variants · 5 GenCC gene-disease records.

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 1B, generalized intermediate

Related subtypes (19): epidermolysis bullosa simplex 1A, generalized severe, epidermolysis bullosa simplex 1C, localized, 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 2A, generalized severe, 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

26 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
264646	NM_017644.3(KLHL24):c.3G>A (p.Met1Ile)	KLHL24	Pathogenic	criteria provided, single submitter
264647	NM_017644.3(KLHL24):c.3G>T (p.Met1Ile)	KLHL24	Pathogenic	criteria provided, single submitter
264648	NM_017644.3(KLHL24):c.1A>G (p.Met1Val)	KLHL24	Pathogenic	criteria provided, multiple submitters, no conflicts
370042	NM_017644.3(KLHL24):c.2T>C (p.Met1Thr)	KLHL24	Pathogenic	criteria provided, single submitter
14612	NM_000526.5(KRT14):c.373C>T (p.Arg125Cys)	KRT14	Pathogenic	criteria provided, multiple submitters, no conflicts
14613	NM_000526.5(KRT14):c.374G>A (p.Arg125His)	KRT14	Pathogenic	criteria provided, multiple submitters, no conflicts
14617	NM_000526.5(KRT14):c.815T>G (p.Met272Arg)	KRT14	Pathogenic	no assertion criteria provided
14621	NM_000526.5(KRT14):c.1243T>C (p.Tyr415His)	KRT14	Pathogenic	criteria provided, single submitter
66315	NM_000526.5(KRT14):c.1231G>T (p.Glu411Ter)	KRT14	Pathogenic	no assertion criteria provided
66341	NM_000526.5(KRT14):c.355A>G (p.Met119Val)	KRT14	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66348	NM_000526.5(KRT14):c.374G>C (p.Arg125Pro)	KRT14	Pathogenic	criteria provided, single submitter
66377	NM_000526.5(KRT14):c.808G>A (p.Val270Met)	KRT14	Pathogenic	criteria provided, single submitter
14641	NM_000424.4(KRT5):c.980T>C (p.Met327Thr)	KRT5	Pathogenic	criteria provided, multiple submitters, no conflicts
14611	NM_000526.5(KRT14):c.1151T>C (p.Leu384Pro)	KRT14	Likely pathogenic	criteria provided, multiple submitters, no conflicts
419836	NM_000526.5(KRT14):c.1163G>A (p.Arg388His)	KRT14	Likely pathogenic	criteria provided, multiple submitters, no conflicts
66369	NM_000526.5(KRT14):c.526-2A>C	KRT14	Likely pathogenic	criteria provided, multiple submitters, no conflicts
438651	NM_000424.4(KRT5):c.1394T>G (p.Val465Gly)	KRT5	Likely pathogenic	no assertion criteria provided
66213	NM_000424.4(KRT5):c.1411C>T (p.Arg471Cys)	KRT5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1338973	NM_000526.5(KRT14):c.373C>A (p.Arg125Ser)	KRT14	Uncertain significance	criteria provided, single submitter
2352985	NM_000526.5(KRT14):c.139G>A (p.Gly47Arg)	KRT14	Uncertain significance	criteria provided, multiple submitters, no conflicts
1668287	NM_000526.5(KRT14):c.188G>A (p.Cys63Tyr)	KRT14	Benign	criteria provided, multiple submitters, no conflicts
66319	NM_000526.5(KRT14):c.1237G>A (p.Ala413Thr)	KRT14	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
66331	NM_000526.5(KRT14):c.189C>T (p.Cys63=)	KRT14	Benign	criteria provided, multiple submitters, no conflicts
66332	NM_000526.5(KRT14):c.193C>T (p.Leu65=)	KRT14	Benign	criteria provided, multiple submitters, no conflicts
66346	NM_000526.5(KRT14):c.369T>C (p.Asn123=)	KRT14	Benign	criteria provided, multiple submitters, no conflicts
781859	NM_000526.5(KRT14):c.166C>T (p.Arg56Cys)	KRT14	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 45 · Orphanet: 14 · 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
KRT14	Definitive	Autosomal recessive	epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive	25
KRT5	Definitive	Autosomal dominant	epidermolysis bullosa simplex 1A, generalized severe	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRT14	Orphanet:69087	Naegeli-Franceschetti-Jadassohn syndrome
KRT14	Orphanet:79396	Autosomal dominant generalized epidermolysis bullosa simplex, severe form
KRT14	Orphanet:79397	Epidermolysis bullosa simplex with mottled pigmentation
KRT14	Orphanet:79399	Autosomal dominant generalized epidermolysis bullosa simplex, intermediate form
KRT14	Orphanet:79400	Localized epidermolysis bullosa simplex
KRT14	Orphanet:86920	Dermatopathia pigmentosa reticularis
KRT14	Orphanet:89838	Autosomal recessive generalized epidermolysis bullosa simplex
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
KLHL24	Orphanet:508529	Intermediate epidermolysis bullosa simplex with cardiomyopathy

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
KRT14	HGNC:6416	ENSG00000186847	P02533	Keratin, type I cytoskeletal 14	gencc,clinvar
KRT5	HGNC:6442	ENSG00000186081	P13647	Keratin, type II cytoskeletal 5	gencc,clinvar
KLHL24	HGNC:25947	ENSG00000114796	Q6TFL4	Kelch-like protein 24	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRT14	Keratin, type I cytoskeletal 14	The nonhelical tail domain is involved in promoting KRT5-KRT14 filaments to self-organize into large bundles and enhances the mechanical properties involved in resilience of keratin intermediate filaments in vitro.
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.
KLHL24	Kelch-like protein 24	Necessary to maintain the balance between intermediate filament stability and degradation, a process that is essential for skin integrity.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRT14	Other/Unknown	no		Keratin_I, IF_conserved, IF_rod_dom
KRT5	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head
KLHL24	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf

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
gingiva	2
gingival epithelium	1
upper arm skin	1
lower esophagus mucosa	1
pharyngeal mucosa	1
blood vessel layer	1
buccal mucosa cell	1
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT14	193	broad	marker	gingiva, gingival epithelium, upper arm skin
KRT5	211	broad	marker	lower esophagus mucosa, pharyngeal mucosa, gingiva
KLHL24	289	ubiquitous	marker	endothelial cell, blood vessel layer, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT5	3,406
KRT14	3,351
KLHL24	1,381

Intra-cohort edges

A	B	Sources
KRT14	KRT5	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRT14	P02533	2
KRT5	P13647	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KLHL24	Q6TFL4	87.69

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 3 evidence-associated genes (2 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 2 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	2	1038.2×	9e-06	KRT14, KRT5
Developmental Lineage of Mammary Gland Myoepithelial Cells	2	543.8×	2e-05	KRT14, KRT5
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	2	278.5×	5e-05	KRT14, KRT5
Developmental Cell Lineages	2	223.9×	5e-05	KRT14, KRT5
Cell junction organization	2	187.2×	6e-05	KRT14, KRT5
Cell-Cell communication	2	137.6×	1e-04	KRT14, KRT5
Formation of the cornified envelope	2	87.8×	2e-04	KRT14, KRT5
Keratinization	2	55.7×	4e-04	KRT14, KRT5
Developmental Lineage of Mammary Stem Cells	1	380.7×	0.003	KRT5
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	228.4×	0.005	KRT5
Developmental Biology	2	14.5×	0.005	KRT14, 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 3 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 organization	3	240.7×	1e-06	KRT14, KRT5, KLHL24
epidermis development	2	140.4×	5e-04	KRT14, KRT5
intermediate filament polymerization	1	5617.3×	9e-04	KRT5
intermediate filament bundle assembly	1	936.2×	0.004	KRT14
response to radiation	1	401.2×	0.008	KRT14
hair cycle	1	312.1×	0.009	KRT14
morphogenesis of an epithelium	1	114.6×	0.017	KRT14
response to mechanical stimulus	1	100.3×	0.017	KRT5
stem cell differentiation	1	100.3×	0.017	KRT14
keratinocyte differentiation	1	82.6×	0.017	KRT14
keratinization	1	78.0×	0.017	KRT5
protein autoubiquitination	1	78.0×	0.017	KLHL24
regulation of protein localization	1	68.5×	0.018	KRT5
regulation of cell migration	1	52.5×	0.022	KRT5
proteasome-mediated ubiquitin-dependent protein catabolic process	1	17.4×	0.060	KLHL24
protein ubiquitination	1	13.8×	0.071	KLHL24

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
KRT14	0	0
KRT5	0	0
KLHL24	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	3	KRT14, KRT5, KLHL24

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
KRT14	0	—
KRT5	0	—
KLHL24	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.