epidermolysis bullosa simplex 1A, generalized severe

Summary

epidermolysis bullosa simplex 1A, generalized severe (MONDO:0007550) is a disease caused by variants in KRT14 and KRT5, with 7 cohort genes. The dominant Reactome pathway is Type I hemidesmosome assembly (5 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal genes: KRT14 (GenCC Definitive), KRT5 (GenCC Definitive)
• Cohort genes: 7
• ClinVar variants: 48
• Phenotypes (HPO): 44

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

44 HPO clinical features (Orphanet curated; top 44 by frequency):

HPO ID	Term	Frequency
HP:0000982	Palmoplantar keratoderma	Very frequent (80-99%)
HP:0001030	Fragile skin	Very frequent (80-99%)
HP:0008066	Abnormal blistering of the skin	Very frequent (80-99%)
HP:0008404	Nail dystrophy	Very frequent (80-99%)
HP:0010783	Erythema	Very frequent (80-99%)
HP:0011354	Generalized abnormality of skin	Very frequent (80-99%)
HP:0000953	Hyperpigmentation of the skin	Frequent (30-79%)
HP:0001056	Milia	Frequent (30-79%)
HP:0001057	Aplasia cutis congenita	Frequent (30-79%)
HP:0001075	Atrophic scars	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001581	Recurrent skin infections	Frequent (30-79%)
HP:0001596	Alopecia	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0006297	Enamel hypoplasia	Frequent (30-79%)
HP:0007589	Aplasia cutis congenita on trunk or limbs	Frequent (30-79%)
HP:0007599	Generalized reticulate brown pigmentation	Frequent (30-79%)
HP:0011471	Gastrostomy tube feeding in infancy	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0100699	Scarring	Frequent (30-79%)
HP:0200097	Oral mucosal blisters	Frequent (30-79%)
HP:0000540	Hypermetropia	Occasional (5-29%)
HP:0000613	Photophobia	Occasional (5-29%)
HP:0001010	Hypopigmentation of the skin	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001363	Craniosynostosis	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001600	Abnormality of the larynx	Occasional (5-29%)
HP:0001601	Laryngomalacia	Occasional (5-29%)
HP:0001609	Hoarse voice	Occasional (5-29%)
HP:0001805	Onychogryposis	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002719	Recurrent infections	Occasional (5-29%)
HP:0002780	Bronchomalacia	Occasional (5-29%)
HP:0003073	Hypoalbuminemia	Occasional (5-29%)
HP:0004313	Decreased circulating antibody level	Occasional (5-29%)
HP:0005483	Abnormal epiglottis morphology	Occasional (5-29%)
HP:0006934	Congenital nystagmus	Occasional (5-29%)
HP:0007483	Depigmentation/hyperpigmentation of skin	Occasional (5-29%)
HP:0007957	Corneal opacity	Occasional (5-29%)
HP:0008944	Distal lower limb amyotrophy	Occasional (5-29%)
HP:0010298	Smooth tongue	Occasional (5-29%)
HP:0100806	Sepsis	Occasional (5-29%)
HP:0006739	Squamous cell carcinoma of the skin	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	epidermolysis bullosa simplex 1A, generalized severe
Mondo ID	MONDO:0007550
OMIM	131760
Orphanet	79396
DOID	DOID:0060735
SNOMED CT	254179000
UMLS	C0079295
MedGen	38194
GARD	0002141
Is cancer (heuristic)	no

Also known as: Dowling-Meara type epidermolysis bullosa simplex · EBS, generalised severe · EBS, generalized severe · EBS-DM · EBSDM · epidermolysis bullosa simplex 1A, generalized severe · epidermolysis bullosa simplex, Dowling-Meara type · epidermolysis bullosa simplex, generalised severe · generalised severe epidermolysis bullosa simplex

Data availability: 48 ClinVar variants · 6 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 1A, generalized severe

Related subtypes (19): 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 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

48 retrieved; paginated sample, class counts are floors:

23 pathogenic, 9 likely pathogenic, 5 benign, 4 uncertain significance, 3 benign/likely benign, 3 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4528341	NM_000494.4(COL17A1):c.2706dup (p.Phe903fs)	COL17A1	Pathogenic	criteria provided, single submitter
1048111	NM_000094.4(COL7A1):c.4550_4554del (p.Ala1517fs)	COL7A1	Pathogenic	criteria provided, multiple submitters, no conflicts
4532191	NM_000094.4(COL7A1):c.1241-2A>G	COL7A1	Pathogenic	criteria provided, single submitter
4532274	NM_000094.4(COL7A1):c.3275A>C (p.Gln1092Pro)	COL7A1	Pathogenic	criteria provided, single submitter
4532275	NM_000094.4(COL7A1):c.6761G>C (p.Gly2254Ala)	COL7A1	Pathogenic	criteria provided, single submitter
4532278	NM_000094.4(COL7A1):c.426G>T (p.Lys142Asn)	COL7A1	Pathogenic	criteria provided, single submitter
4533181	NM_000094.4(COL7A1):c.5632G>T (p.Gly1878Ter)	COL7A1	Pathogenic	criteria provided, single submitter
4533374	NM_000094.4(COL7A1):c.5602G>T (p.Glu1868Ter)	COL7A1	Pathogenic	criteria provided, single submitter
1321191	NM_000526.5(KRT14):c.1242_1259del (p.Tyr415_Glu420del)	KRT14	Pathogenic	no assertion criteria provided
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
14619	NM_000526.5(KRT14):c.356T>C (p.Met119Thr)	KRT14	Pathogenic	criteria provided, multiple submitters, no conflicts
14622	NM_000526.5(KRT14):c.1256T>A (p.Leu419Gln)	KRT14	Pathogenic	no assertion criteria provided
14628	NM_000526.5(KRT14):c.368A>G (p.Asn123Ser)	KRT14	Pathogenic	criteria provided, single submitter
4280327	NM_000526.5(KRT14):c.1225del (p.Glu409fs)	KRT14	Pathogenic	criteria provided, single submitter
66309	NM_000526.5(KRT14):c.1186C>T (p.Gln396Ter)	KRT14	Pathogenic/Likely pathogenic	criteria provided, single submitter
66323	NM_000526.5(KRT14):c.1246del (p.Arg416fs)	KRT14	Pathogenic	no assertion criteria provided
66348	NM_000526.5(KRT14):c.374G>C (p.Arg125Pro)	KRT14	Pathogenic	criteria provided, single submitter
66382	NM_000526.5(KRT14):c.915G>A (p.Trp305Ter)	KRT14	Pathogenic	criteria provided, multiple submitters, no conflicts
14641	NM_000424.4(KRT5):c.980T>C (p.Met327Thr)	KRT5	Pathogenic	criteria provided, multiple submitters, no conflicts
14650	NM_000424.4(KRT5):c.541T>C (p.Ser181Pro)	KRT5	Pathogenic	criteria provided, single submitter
21174	NM_000424.4(KRT5):c.1429G>A (p.Glu477Lys)	KRT5	Pathogenic	criteria provided, multiple submitters, no conflicts
66273	NM_000424.4(KRT5):c.579C>A (p.Asn193Lys)	KRT5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370862	NM_000228.3(LAMB3):c.2011del (p.Leu671fs)	LAMB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66215	NM_000424.4(KRT5):c.1427G>A (p.Gly476Asp)	LOC126861525	Pathogenic	criteria provided, multiple submitters, no conflicts
4528342	NM_201384.3(PLEC):c.954G>A (p.Trp318Ter)	PLEC	Pathogenic	criteria provided, single submitter
4294547	NM_000421.5(KRT10):c.359G>A (p.Gly120Asp)	KRT10	Likely pathogenic	criteria provided, single submitter
14611	NM_000526.5(KRT14):c.1151T>C (p.Leu384Pro)	KRT14	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2627472	NM_000526.5(KRT14):c.614del (p.Glu205fs)	KRT14	Likely pathogenic	criteria provided, single submitter
3064710	NM_000526.5(KRT14):c.815T>A (p.Met272Lys)	KRT14	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 45 · Orphanet: 38 · 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
COL17A1	Orphanet:251393	Localized junctional epidermolysis bullosa
COL17A1	Orphanet:293381	Epithelial recurrent erosion dystrophy
COL17A1	Orphanet:79402	Intermediate generalized junctional epidermolysis bullosa
COL17A1	Orphanet:79406	Late-onset junctional epidermolysis bullosa
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
KRT10	Orphanet:281139	Annular epidermolytic ichthyosis
KRT10	Orphanet:281190	Congenital reticular ichthyosiform erythroderma
KRT10	Orphanet:312	Autosomal dominant epidermolytic ichthyosis
KRT10	Orphanet:512103	Autosomal recessive epidermolytic ichthyosis
LAMB3	Orphanet:100031	Hypoplastic amelogenesis imperfecta
LAMB3	Orphanet:79402	Intermediate generalized junctional epidermolysis bullosa
LAMB3	Orphanet:79404	Severe generalized junctional epidermolysis bullosa
PLEC	Orphanet:1114	Aplasia cutis congenita
PLEC	Orphanet:158684	Epidermolysis bullosa simplex with pyloric atresia
PLEC	Orphanet:254361	Plectin-related limb-girdle muscular dystrophy R17
PLEC	Orphanet:257	Epidermolysis bullosa simplex with muscular dystrophy
PLEC	Orphanet:79401	PLEC-related intermediate epidermolysis bullosa simplex without extracutaneous involvement

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

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
COL17A1	HGNC:2194	ENSG00000065618	Q9UMD9	Collagen alpha-1(XVII) chain	clinvar
COL7A1	HGNC:2214	ENSG00000114270	Q02388	Collagen alpha-1(VII) chain	clinvar
KRT10	HGNC:6413	ENSG00000186395	P13645	Keratin, type I cytoskeletal 10	clinvar
LAMB3	HGNC:6490	ENSG00000196878	Q13751	Laminin subunit beta-3	clinvar
PLEC	HGNC:9069	ENSG00000178209	Q15149	Plectin	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.
COL17A1	Collagen alpha-1(XVII) chain	May play a role in the integrity of hemidesmosome and the attachment of basal keratinocytes to the underlying basement membrane.
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…
KRT10	Keratin, type I cytoskeletal 10	Plays a role in the establishment of the epidermal barrier on plantar skin.
LAMB3	Laminin subunit beta-3	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
PLEC	Plectin	Interlinks intermediate filaments with microtubules and microfilaments and anchors intermediate filaments to desmosomes or hemidesmosomes.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 5 · Druggable fraction: 0.14

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
Antibody/Immunoglobulin	1	4.2×	0.341
Scaffold/PPI	1	2.5×	0.341
Other/Unknown	5	1.3×	0.341

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
COL17A1	Other/Unknown	no		Collagen, Collagen_superfamily
COL7A1	Antibody/Immunoglobulin	yes		VWF_A, Kunitz_BPTI, FN3_dom
KRT10	Other/Unknown	no		Keratin_I, IF_conserved, IF_rod_dom
LAMB3	Other/Unknown	no		EGF, LE_dom, Laminin_N
PLEC	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Actinin_actin-bd_CS

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingiva	2
gingival epithelium	2
skin of abdomen	2
skin of leg	2
upper arm skin	1
lower esophagus mucosa	1
pharyngeal mucosa	1
zone of skin	1
stromal cell of endometrium	1
mammalian vulva	1
penis	1
upper leg skin	1
cartilage tissue	1
periodontal ligament	1
hindlimb stylopod muscle	1
sural nerve	1
tibial nerve	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
COL17A1	182	broad	marker	skin of abdomen, skin of leg, zone of skin
COL7A1	267	ubiquitous	marker	stromal cell of endometrium, skin of abdomen, skin of leg
KRT10	299	broad	marker	upper leg skin, penis, mammalian vulva
LAMB3	215	ubiquitous	marker	cartilage tissue, periodontal ligament, gingival epithelium
PLEC	283	ubiquitous	marker	sural nerve, hindlimb stylopod muscle, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 9.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLEC	3,529
KRT5	3,406
KRT14	3,351
KRT10	2,304
COL17A1	1,769
COL7A1	1,767
LAMB3	1,697

Intra-cohort edges

A	B	Sources
COL17A1	KRT14	string_interaction
COL17A1	KRT5	string_interaction
COL17A1	LAMB3	string_interaction
COL17A1	PLEC	string_interaction
COL7A1	LAMB3	biogrid_interaction, string_interaction
KRT10	KRT5	biogrid_interaction
KRT14	KRT5	intact, string_interaction
KRT14	PLEC	intact, string_interaction
KRT5	PLEC	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLEC	Q15149	14
KRT10	P13645	6
KRT14	P02533	2
KRT5	P13647	2
COL17A1	Q9UMD9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LAMB3	Q13751	78.55
COL7A1	Q02388

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 35. Enrichment computed across 7 evidence-associated genes (7 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 7 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	5	741.6×	2e-13	KRT14, KRT5, COL17A1, LAMB3, PLEC
Assembly of collagen fibrils and other multimeric structures	4	114.5×	3e-07	COL17A1, COL7A1, LAMB3, PLEC
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	3	119.4×	2e-05	KRT14, KRT5, KRT10
Developmental Cell Lineages	3	96.0×	3e-05	KRT14, KRT5, KRT10
Cell junction organization	3	80.2×	3e-05	KRT14, KRT5, LAMB3
Cell-Cell communication	3	59.0×	7e-05	KRT14, KRT5, LAMB3
Anchoring fibril formation	2	217.5×	2e-04	COL7A1, LAMB3
Formation of the cornified envelope	3	37.6×	2e-04	KRT14, KRT5, KRT10
Developmental Lineage of Mammary Gland Myoepithelial Cells	2	155.4×	3e-04	KRT14, KRT5
Laminin interactions	2	108.8×	5e-04	COL7A1, LAMB3
Keratinization	3	23.9×	6e-04	KRT14, KRT5, KRT10
Collagen chain trimerization	2	74.2×	9e-04	COL17A1, COL7A1
Collagen degradation	2	50.2×	0.002	COL17A1, COL7A1
Collagen biosynthesis and modifying enzymes	2	48.7×	0.002	COL17A1, COL7A1
Caspase-mediated cleavage of cytoskeletal proteins	1	135.9×	0.017	PLEC
Developmental Lineage of Mammary Stem Cells	1	108.8×	0.019	KRT5
Developmental Biology	3	6.2×	0.019	KRT14, KRT5, KRT10
MET promotes cell motility	1	85.9×	0.022	LAMB3
Fibronectin matrix formation	1	81.6×	0.022	COL7A1
Attachment of bacteria to epithelial cells	1	70.9×	0.024	LAMB3
Collagen formation	1	65.3×	0.024	LAMB3
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	65.3×	0.024	KRT5
MET activates PTK2 signaling	1	54.4×	0.028	LAMB3
Cargo concentration in the ER	1	48.0×	0.030	COL7A1
Signaling by MET	1	45.3×	0.030	LAMB3
Formation of the dystrophin-glycoprotein complex (DGC)	1	44.1×	0.030	LAMB3
Developmental Lineage of Pancreatic Ductal Cells	1	32.6×	0.039	LAMB3
COPII-mediated vesicle transport	1	23.3×	0.053	COL7A1
Non-integrin membrane-ECM interactions	1	22.1×	0.054	LAMB3
Integrin cell surface interactions	1	19.2×	0.059	COL7A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
epidermis development	5	150.5×	2e-09	KRT14, KRT5, COL17A1, COL7A1, LAMB3
intermediate filament organization	4	137.6×	2e-07	KRT14, KRT5, KRT10, PLEC
hemidesmosome assembly	2	687.8×	5e-05	COL17A1, PLEC
endodermal cell differentiation	2	141.6×	0.001	COL7A1, LAMB3
morphogenesis of an epithelium	2	98.3×	0.002	KRT14, KRT10
protein-containing complex organization	1	2407.4×	0.002	PLEC
intermediate filament polymerization	1	2407.4×	0.002	KRT5
actomyosin contractile ring assembly actin filament organization	1	2407.4×	0.002	PLEC
keratinocyte differentiation	2	70.8×	0.002	KRT14, KRT10
skeletal myofibril assembly	1	1203.7×	0.004	PLEC
leukocyte migration involved in immune response	1	802.5×	0.005	PLEC
cellular response to hydrostatic pressure	1	802.5×	0.005	PLEC
positive regulation of epidermis development	1	481.5×	0.008	KRT10
tight junction organization	1	481.5×	0.008	PLEC
intermediate filament bundle assembly	1	401.2×	0.008	KRT14
keratinocyte development	1	218.9×	0.014	PLEC
peripheral nervous system myelin maintenance	1	218.9×	0.014	PLEC
cellular response to fluid shear stress	1	185.2×	0.015	PLEC
response to radiation	1	172.0×	0.015	KRT14
T cell chemotaxis	1	160.5×	0.015	PLEC
regulation of vascular permeability	1	160.5×	0.015	PLEC
protein heterotetramerization	1	150.5×	0.015	KRT10
cornification	1	150.5×	0.015	KRT10
hair cycle	1	133.8×	0.015	KRT14
intermediate filament cytoskeleton organization	1	133.8×	0.015	PLEC
fibroblast migration	1	120.4×	0.015	PLEC
respiratory electron transport chain	1	120.4×	0.015	PLEC
myoblast differentiation	1	120.4×	0.015	PLEC
transmission of nerve impulse	1	92.6×	0.019	PLEC
cardiac muscle cell development	1	89.2×	0.019	PLEC

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 7

Druggability breadth: 3 of 7 evidence-associated genes (43%) 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
COL17A1	0	0
COL7A1	0	0
KRT10	0	0
LAMB3	0	0
PLEC	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
PLEC	12	Binding:12

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; 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	1	COL7A1
E	Difficult family or no structure, no drug	6	KRT14, KRT5, COL17A1, KRT10, LAMB3, PLEC

Undrugged target profiles

7 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	—
COL17A1	0	—
COL7A1	0	—
KRT10	0	—
LAMB3	0	—
PLEC	12	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.