Epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive

Summary

Epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive (MONDO:0014014) is a disease caused by EXPH5 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: EXPH5 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive
Mondo ID	MONDO:0014014
OMIM	615028
Orphanet	412189
UMLS	C3554367
MedGen	767281
GARD	0017691
Is cancer (heuristic)	no

Also known as: EBNS · EBS-AR exophilin 5 · epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive · epidermolysis bullosa simplex due to exophilin 5 deficiency · epidermolysis bullosa, nonspecific, autosomal recessive

Data availability: 20 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 4, localized or generalized intermediate, autosomal recessive

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 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

20 retrieved; paginated sample, class counts are floors:

8 pathogenic, 4 benign, 3 likely pathogenic, 2 uncertain significance, 2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1304967	NM_015065.3(EXPH5):c.1395del (p.Phe466fs)	EXPH5	Pathogenic	no assertion criteria provided
1304968	NM_015065.3(EXPH5):c.2897del (p.Pro966fs)	EXPH5	Pathogenic	no assertion criteria provided
1304969	NM_015065.3(EXPH5):c.1947dup (p.Thr650fs)	EXPH5	Pathogenic	no assertion criteria provided
1304970	NM_015065.3(EXPH5):c.2249C>A (p.Ser750Ter)	EXPH5	Pathogenic	no assertion criteria provided
1304971	NM_015065.3(EXPH5):c.3650T>A (p.Leu1217Ter)	EXPH5	Pathogenic	no assertion criteria provided
1304972	NM_015065.3(EXPH5):c.2542del (p.His848fs)	EXPH5	Pathogenic	no assertion criteria provided
1304973	NM_015065.3(EXPH5):c.3917C>G (p.Ser1306Ter)	EXPH5	Pathogenic	no assertion criteria provided
1322843	NM_015065.3(EXPH5):c.939del (p.Asn314fs)	EXPH5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265125	NM_015065.3(EXPH5):c.5786del (p.Pro1929fs)	EXPH5	Pathogenic	criteria provided, multiple submitters, no conflicts
3779631	NM_015065.3(EXPH5):c.4483dup (p.Met1495fs)	EXPH5	Likely pathogenic	criteria provided, single submitter
4081381	NM_015065.3(EXPH5):c.89_99del (p.Glu30fs)	EXPH5	Likely pathogenic	criteria provided, single submitter
4081382	NM_015065.3(EXPH5):c.644T>A (p.Leu215Ter)	EXPH5	Likely pathogenic	criteria provided, single submitter
1698844	NM_015065.3(EXPH5):c.4917C>A (p.Cys1639Ter)	EXPH5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1805039	NM_015065.3(EXPH5):c.5422C>T (p.Arg1808Ter)	EXPH5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029346	NM_015065.3(EXPH5):c.2890C>T (p.His964Tyr)	EXPH5	Uncertain significance	criteria provided, single submitter
3064914	NM_015065.3(EXPH5):c.2525G>A (p.Arg842Lys)	EXPH5	Uncertain significance	criteria provided, single submitter
1227267	NM_015065.3(EXPH5):c.4987G>A (p.Gly1663Arg)	EXPH5	Benign	criteria provided, multiple submitters, no conflicts
1253296	NM_015065.3(EXPH5):c.2027G>A (p.Ser676Asn)	EXPH5	Benign	criteria provided, multiple submitters, no conflicts
1274464	NM_015065.3(EXPH5):c.55A>G (p.Arg19Gly)	EXPH5	Benign	criteria provided, multiple submitters, no conflicts
1285243	NM_015065.3(EXPH5):c.5922A>G (p.Thr1974=)	EXPH5	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
EXPH5	Strong	Autosomal recessive	epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EXPH5	Orphanet:412189	Epidermolysis bullosa simplex due to exophilin 5 deficiency

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
EXPH5	HGNC:30578	ENSG00000110723	Q8NEV8	Exophilin-5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EXPH5	Exophilin-5	May act as Rab effector protein and play a role in vesicle trafficking.

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)
EXPH5	Other/Unknown	no		Rab_BD, EXPH5

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
mucosa of paranasal sinus	1
skin of hip	1
tongue squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EXPH5	247	broad	marker	tongue squamous epithelium, skin of hip, mucosa of paranasal sinus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EXPH5	726

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EXPH5	Q8NEV8	36.39

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
keratinocyte development	1	1532.0×	0.003	EXPH5
multivesicular body sorting pathway	1	802.5×	0.003	EXPH5
positive regulation of exocytosis	1	601.9×	0.003	EXPH5
positive regulation of protein secretion	1	343.9×	0.004	EXPH5
intracellular protein transport	1	64.8×	0.015	EXPH5

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
EXPH5	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	EXPH5

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)
EXPH5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.