Hailey-Hailey disease

Summary

Hailey-Hailey disease (MONDO:0008218) is a disease caused by ATP2C1 (GenCC Definitive), with 1 cohort gene and 5 clinical trials. Top therapeutic interventions include doxycycline anhydrous and guselkumab.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: ATP2C1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 86
• Phenotypes (HPO): 5
• Clinical trials: 5

Clinical features

Signs & symptoms

Clinical features (HPO)

5 HPO clinical features (Orphanet curated; top 5 by frequency):

HPO ID	Term	Frequency
HP:0000962	Hyperkeratosis	Very frequent (80-99%)
HP:0010783	Erythema	Very frequent (80-99%)
HP:0100792	Acantholysis	Very frequent (80-99%)
HP:0200041	Skin erosion	Very frequent (80-99%)
HP:0200037	Skin vesicle	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Hailey-Hailey disease
Mondo ID	MONDO:0008218
MeSH	D016506
OMIM	169600
Orphanet	2841
DOID	DOID:0050429
ICD-11	818400628
NCIT	C82865
SNOMED CT	79468000
UMLS	C0085106
MedGen	43100
GARD	0006559
NORD	1211
Is cancer (heuristic)	no

Also known as: BCPM · benign chronic familial pemphigus of Hailey-Hailey · benign chronic pemphigus · benign familial pemphigus · familial benign pemphigus · Hailey-Hailey disease · pemphigus, benign familial

Data availability: 86 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 › dermatitis › autoimmune bullous skin disease › pemphigus › Hailey-Hailey disease

Related subtypes (5): pemphigoid gestationis, pemphigus vulgaris, herpetiform pemphigus, pemphigus erythematosus, pemphigus foliaceus

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

86 retrieved; paginated sample, class counts are floors:

44 uncertain significance, 18 benign, 11 pathogenic, 4 likely pathogenic, 3 conflicting classifications of pathogenicity, 3 likely benign, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1264346	NM_001378687.1(ATP2C1):c.900-1G>C	ATP2C1	Pathogenic	no assertion criteria provided
2097916	NM_001378687.1(ATP2C1):c.1356C>A (p.Tyr452Ter)	ATP2C1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372308	NM_001378687.1(ATP2C1):c.2375_2378del (p.Phe792fs)	ATP2C1	Pathogenic	criteria provided, multiple submitters, no conflicts
4686705	NM_001378687.1(ATP2C1):c.1308+1G>T	ATP2C1	Pathogenic	criteria provided, single submitter
5581	NM_001378687.1(ATP2C1):c.769_772dup (p.Leu258fs)	ATP2C1	Pathogenic	no assertion criteria provided
5582	NM_001378687.1(ATP2C1):c.910G>A (p.Ala304Thr)	ATP2C1	Pathogenic	no assertion criteria provided
5583	NM_001378687.1(ATP2C1):c.1402C>T (p.Arg468Ter)	ATP2C1	Pathogenic	criteria provided, single submitter
5585	NM_001378687.1(ATP2C1):c.900-1G>A	ATP2C1	Pathogenic	no assertion criteria provided
5586	NM_001378687.1(ATP2C1):c.1469G>T (p.Cys490Phe)	ATP2C1	Pathogenic	no assertion criteria provided
5587	NM_001378687.1(ATP2C1):c.2460del (p.Met820fs)	ATP2C1	Pathogenic	no assertion criteria provided
5588	NM_001378687.1(ATP2C1):c.1751T>C (p.Leu584Pro)	ATP2C1	Pathogenic	no assertion criteria provided
5589	NM_001378687.1(ATP2C1):c.2126+1G>A	ATP2C1	Pathogenic	criteria provided, single submitter
1878432	NM_001378687.1(ATP2C1):c.1840_1844del (p.Val614fs)	ATP2C1	Likely pathogenic	no assertion criteria provided
1878433	NM_001378687.1(ATP2C1):c.1840-4del	ATP2C1	Likely pathogenic	no assertion criteria provided
1878434	NM_001378687.1(ATP2C1):c.1570+3A>C	ATP2C1	Likely pathogenic	no assertion criteria provided
4086229	NM_001378687.1(ATP2C1):c.1764del (p.Thr590fs)	ATP2C1	Likely pathogenic	criteria provided, single submitter
3382309	NM_001378687.1(ATP2C1):c.661A>G (p.Thr221Ala)	ATP2C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899637	NM_001378687.1(ATP2C1):c.635C>T (p.Ser212Leu)	ATP2C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903304	NM_001378687.1(ATP2C1):c.2439A>G (p.Thr813=)	ATP2C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3064721	NM_001378687.1(ATP2C1):c.2167A>G (p.Met723Val)	ATP2C1	Uncertain significance	criteria provided, single submitter
343315	NM_001378687.1(ATP2C1):c.-66C>T	ATP2C1	Uncertain significance	criteria provided, single submitter
343316	NM_001378687.1(ATP2C1):c.-64A>G	ATP2C1	Uncertain significance	criteria provided, single submitter
343321	NM_001378687.1(ATP2C1):c.532-6C>T	ATP2C1	Uncertain significance	criteria provided, single submitter
343325	NM_001378687.1(ATP2C1):c.996G>A (p.Val332=)	ATP2C1	Uncertain significance	criteria provided, single submitter
343330	NM_001378687.1(ATP2C1):c.1905C>A (p.Asn635Lys)	ATP2C1	Uncertain significance	criteria provided, single submitter
343333	NM_001378687.1(ATP2C1):c.2694T>C (p.Val898=)	ATP2C1	Uncertain significance	criteria provided, single submitter
343334	NM_001378687.1(ATP2C1):c.*127A>G	ATP2C1	Uncertain significance	criteria provided, single submitter
343337	NM_001378687.1(ATP2C1):c.*343T>A	ATP2C1	Uncertain significance	criteria provided, single submitter
343340	NM_001378687.1(ATP2C1):c.*881A>G	ATP2C1	Uncertain significance	criteria provided, single submitter
343341	NM_001378687.1(ATP2C1):c.*946T>G	ATP2C1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
ATP2C1	Definitive	Autosomal dominant	Hailey-Hailey disease	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP2C1	Orphanet:2841	Hailey-Hailey disease

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
ATP2C1	HGNC:13211	ENSG00000017260	P98194	Calcium-transporting ATPase type 2C member 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP2C1	Calcium-transporting ATPase type 2C member 1	ATP-driven pump that supplies the Golgi apparatus with Ca(2+) and Mn(2+) ions, both essential cofactors for processing and trafficking of newly synthesized proteins in the secretory pathway.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP2C1	Transcription factor	no	7.2.2.10	P_typ_ATPase, ATPase_P-typ_cation-transptr_N, ATPase_P-typ_cation-transptr_C

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
cortical plate	1
secondary oocyte	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP2C1	289	ubiquitous	marker	cortical plate, secondary oocyte, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP2C1	2,410

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP2C1	P98194	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Ion transport by P-type ATPases	1	207.6×	0.014	ATP2C1
Ion channel transport	1	96.0×	0.016	ATP2C1
Transport of small molecules	1	25.1×	0.040	ATP2C1

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
Golgi calcium ion homeostasis	1	8426.0×	5e-04	ATP2C1
Golgi calcium ion transport	1	8426.0×	5e-04	ATP2C1
trans-Golgi network membrane organization	1	8426.0×	5e-04	ATP2C1
intracellular manganese ion homeostasis	1	3370.4×	9e-04	ATP2C1
positive regulation of Golgi to plasma membrane protein transport	1	2808.7×	9e-04	ATP2C1
manganese ion transport	1	2106.5×	0.001	ATP2C1
calcium-dependent cell-cell adhesion	1	481.5×	0.004	ATP2C1
epidermis development	1	210.7×	0.007	ATP2C1
calcium ion transmembrane transport	1	210.7×	0.007	ATP2C1
calcium ion transport	1	181.2×	0.007	ATP2C1
intracellular calcium ion homeostasis	1	145.3×	0.008	ATP2C1
actin cytoskeleton organization	1	79.1×	0.014	ATP2C1
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.014	ATP2C1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP2C1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ATP2C1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP2C1	7.2.2.10	P-type Ca2+ transporter

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	ATP2C1

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)
ATP2C1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06651489	PHASE2	RECRUITING	Efficacy of Guselkumab in Treating Hailey Hailey Disease
NCT02782702	PHASE1	COMPLETED	Evaluation of the Improvement of Quality of Life of Patients Suffering From Hailey Hailey or Darier Disease After Injections of Botulism Toxin Into Large Folds.
NCT00074685	Not specified	COMPLETED	National Registry for Ichthyosis and Related Disorders
NCT03849989	Not specified	COMPLETED	M. Hailey-Hailey: hSPCA1 Expression and Skin Structure Upon Laser Therapy
NCT05007223	Not specified	COMPLETED	Skin Microbiome Profile in Hailey-Hailey Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DOXYCYCLINE ANHYDROUS	4	1
GUSELKUMAB	4	1