Darier disease

Summary

Darier disease (MONDO:0007417) is a disease caused by ATP2A2 (GenCC Definitive), with 1 cohort gene and 4 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: ATP2A2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 130
• Phenotypes (HPO): 25
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	3.4	Europe	Validated
Annual incidence	1-9 / 1 000 000	0.31	Singapore	Validated
Point prevalence	1-9 / 100 000	3	United Kingdom	Validated
Point prevalence	1-9 / 100 000	1	Denmark	Validated
Point prevalence	1-9 / 100 000	3.8	Slovenia	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0000989	Pruritus	Very frequent (80-99%)
HP:0001034	Hypermelanotic macule	Very frequent (80-99%)
HP:0001597	Abnormality of the nail	Very frequent (80-99%)
HP:0008410	Subungual hyperkeratotic fragments	Very frequent (80-99%)
HP:0045059	Hyperkeratotic papule	Very frequent (80-99%)
HP:0200016	Acrokeratosis	Very frequent (80-99%)
HP:0000498	Blepharitis	Frequent (30-79%)
HP:0000982	Palmoplantar keratoderma	Frequent (30-79%)
HP:0001000	Abnormality of skin pigmentation	Frequent (30-79%)
HP:0001072	Thickened skin	Frequent (30-79%)
HP:0001097	Keratoconjunctivitis sicca	Frequent (30-79%)
HP:0001595	Abnormality of the hair	Frequent (30-79%)
HP:0001808	Fragile nails	Frequent (30-79%)
HP:0005212	Anal mucosal leukoplakia	Frequent (30-79%)
HP:0010610	Palmar pits	Frequent (30-79%)
HP:0010612	Plantar pits	Frequent (30-79%)
HP:0031288	Cobblestone-like hyperkeratosis	Frequent (30-79%)
HP:6001074	Longitudinal erythronychia	Frequent (30-79%)
HP:0000716	Depression	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0007302	Bipolar affective disorder	Occasional (5-29%)
HP:0011859	Punctate keratitis	Occasional (5-29%)
HP:0012733	Macule	Occasional (5-29%)
HP:0200037	Skin vesicle	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Darier disease
Mondo ID	MONDO:0007417
MeSH	D007644
OMIM	124200
Orphanet	218
DOID	DOID:2734
ICD-11	643994486
NCIT	C84665
SNOMED CT	48611009
UMLS	C0022595
MedGen	5956
GARD	0006243
MedDRA	10023369
NORD	1329
Is cancer (heuristic)	no

Also known as: DAR · Darier disease · Darier White disease · Darier’s disease · Darier-White disease · Keratosis Follicularis · keratosis follicularis

Data availability: 130 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › epidermal disease › Darier disease

Related subtypes (24): porokeratosis, absence of fingerprints-congenital milia syndrome, hyperkeratosis lenticularis perstans, keratolytic winter erythema, Hailey-Hailey disease, VPS13A-related neurodegenerative disease, acanthosis nigricans-insulin resistance-muscle cramps-acral enlargement syndrome, keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome, seborrhea-like dermatitis with psoriasiform elements, psoriasis 14, pustular, palmoplantar pustulosis, hereditary poikiloderma, congenital erosive and vesicular dermatosis, neonatal inflammatory skin and bowel disease, 13q12.3 microdeletion syndrome, zinc-responsive necrolytic acral erythema, keratosis pilaris atrophicans, ichthyosis, erythrokeratoderma, hereditary palmoplantar keratoderma, inherited epidermolysis bullosa, punctate acrokeratoderma freckle-like pigmentation, aquagenic palmoplantar keratoderma, phrynoderma

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

130 retrieved; paginated sample, class counts are floors:

52 uncertain significance, 30 benign, 20 likely pathogenic, 10 pathogenic, 7 likely benign, 5 benign/likely benign, 5 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17789	NM_170665.4(ATP2A2):c.68G>A (p.Gly23Glu)	ATP2A2	Pathogenic	criteria provided, single submitter
17790	NM_170665.4(ATP2A2):c.322C>T (p.Gln108Ter)	ATP2A2	Pathogenic	no assertion criteria provided
17792	NM_170665.4(ATP2A2):c.2300A>G (p.Asn767Ser)	ATP2A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17794	NM_170665.4(ATP2A2):c.1678T>C (p.Cys560Arg)	ATP2A2	Pathogenic	no assertion criteria provided
17795	NM_170665.4(ATP2A2):c.137-13_137-12insNNNNNNNNNNNNNNNNNN	ATP2A2	Pathogenic	no assertion criteria provided
17796	NM_170665.4(ATP2A2):c.2258ACA[2] (p.Asn755del)	ATP2A2	Pathogenic	no assertion criteria provided
17800	NM_170665.4(ATP2A2):c.392G>A (p.Arg131Gln)	ATP2A2	Pathogenic	criteria provided, single submitter
2507396	NM_170665.4(ATP2A2):c.1013C>T (p.Ser338Phe)	ATP2A2	Pathogenic	criteria provided, single submitter
2735974	NM_170665.4(ATP2A2):c.2104G>A (p.Asp702Asn)	ATP2A2	Pathogenic	criteria provided, multiple submitters, no conflicts
3255563	NM_170665.4(ATP2A2):c.1006_1010delinsTTCCAAGG (p.Leu336_Pro337delinsPheGlnGly)	ATP2A2	Pathogenic	criteria provided, single submitter
1190253	NM_170665.4(ATP2A2):c.2039C>T (p.Pro680Leu)	LOC126861637	Pathogenic	criteria provided, multiple submitters, no conflicts
17791	NM_170665.4(ATP2A2):c.544+1G>A	ATP2A2	Likely pathogenic	criteria provided, single submitter
2627605	NM_170665.4(ATP2A2):c.1010del (p.Pro337fs)	ATP2A2	Likely pathogenic	criteria provided, single submitter
3061851	NM_170665.4(ATP2A2):c.220-1G>A	ATP2A2	Likely pathogenic	criteria provided, single submitter
3359244	NM_170665.4(ATP2A2):c.1060G>C (p.Gly354Arg)	ATP2A2	Likely pathogenic	no assertion criteria provided
3359246	NM_170665.4(ATP2A2):c.1454_1455dup (p.Glu486Ter)	ATP2A2	Likely pathogenic	no assertion criteria provided
3359247	NM_170665.4(ATP2A2):c.1472_1473del (p.Arg491fs)	ATP2A2	Likely pathogenic	no assertion criteria provided
3359248	NM_170665.4(ATP2A2):c.1655dup (p.Gly552_Ser553insTer)	ATP2A2	Likely pathogenic	no assertion criteria provided
3359250	NM_170665.4(ATP2A2):c.2161T>C (p.Ser721Pro)	ATP2A2	Likely pathogenic	no assertion criteria provided
3359251	NM_170665.4(ATP2A2):c.2315_2318delTCTG (p.Cys773fs)	ATP2A2	Likely pathogenic	no assertion criteria provided
3359252	NM_170665.4(ATP2A2):c.2318+2T>C	ATP2A2	Likely pathogenic	no assertion criteria provided
3359254	NM_170665.4(ATP2A2):c.170_171dup (p.Glu58fs)	ATP2A2	Likely pathogenic	no assertion criteria provided
3359255	NM_170665.4(ATP2A2):c.269A>T (p.Glu90Val)	ATP2A2	Likely pathogenic	no assertion criteria provided
3359257	NM_170665.4(ATP2A2):c.689_692del (p.Thr230fs)	ATP2A2	Likely pathogenic	no assertion criteria provided
3359258	NM_170665.4(ATP2A2):c.712G>T (p.Glu238Ter)	ATP2A2	Likely pathogenic	no assertion criteria provided
3359259	NM_170665.4(ATP2A2):c.912dup (p.Ala305fs)	ATP2A2	Likely pathogenic	no assertion criteria provided
3359260	NM_170665.4(ATP2A2):c.943A>T (p.Ile315Phe)	ATP2A2	Likely pathogenic	no assertion criteria provided
3774488	NM_170665.4(ATP2A2):c.2741_2741+1delinsAA	ATP2A2	Likely pathogenic	criteria provided, single submitter
4796542	NM_170665.4(ATP2A2):c.2788_2790dup (p.Ile930_Trp931insIle)	ATP2A2	Likely pathogenic	criteria provided, single submitter
807380	NM_170665.4(ATP2A2):c.2381T>A (p.Val794Asp)	ATP2A2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
ATP2A2	Definitive	Autosomal dominant	Darier disease	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP2A2	Orphanet:218	Darier disease
ATP2A2	Orphanet:79151	Acrokeratosis verruciformis of Hopf

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
ATP2A2	HGNC:812	ENSG00000174437	P16615	Sarcoplasmic/endoplasmic reticulum calcium ATPase 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP2A2	Sarcoplasmic/endoplasmic reticulum calcium ATPase 2	This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen.

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)
ATP2A2	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIA

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
biceps brachii	1
heart right ventricle	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP2A2	304	ubiquitous	marker	heart right ventricle, skeletal muscle tissue of biceps brachii, biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP2A2	807

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP2A2	P16615	15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. 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
Reduction of cytosolic Ca++ levels	1	951.7×	0.007	ATP2A2
Platelet calcium homeostasis	1	713.8×	0.007	ATP2A2
Pre-NOTCH Processing in Golgi	1	634.4×	0.007	ATP2A2
Pre-NOTCH Expression and Processing	1	368.4×	0.010	ATP2A2
Platelet homeostasis	1	278.5×	0.010	ATP2A2
Ion transport by P-type ATPases	1	207.6×	0.010	ATP2A2
Ion homeostasis	1	203.9×	0.010	ATP2A2
Signaling by NOTCH	1	175.7×	0.010	ATP2A2
Cardiac conduction	1	108.8×	0.014	ATP2A2
Ion channel transport	1	96.0×	0.015	ATP2A2
Muscle contraction	1	77.2×	0.016	ATP2A2
Hemostasis	1	36.0×	0.032	ATP2A2
Transport of small molecules	1	25.1×	0.043	ATP2A2
Signal Transduction	1	10.2×	0.098	ATP2A2

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
ER-nucleus signaling pathway	1	16852.0×	9e-04	ATP2A2
regulation of calcium ion-dependent exocytosis of neurotransmitter	1	8426.0×	9e-04	ATP2A2
calcium ion transport from cytosol to endoplasmic reticulum	1	8426.0×	9e-04	ATP2A2
positive regulation of endoplasmic reticulum calcium ion concentration	1	5617.3×	9e-04	ATP2A2
organelle localization by membrane tethering	1	5617.3×	9e-04	ATP2A2
calcium ion import into sarcoplasmic reticulum	1	5617.3×	9e-04	ATP2A2
negative regulation of heart contraction	1	4213.0×	0.001	ATP2A2
sarcoplasmic reticulum calcium ion transport	1	3370.4×	0.001	ATP2A2
T-tubule organization	1	2808.7×	0.001	ATP2A2
transition between fast and slow fiber	1	2407.4×	0.001	ATP2A2
autophagosome membrane docking	1	2407.4×	0.001	ATP2A2
regulation of cardiac muscle cell membrane potential	1	2407.4×	0.001	ATP2A2
obsolete mitochondrion-endoplasmic reticulum membrane tethering	1	2106.5×	0.001	ATP2A2
regulation of cardiac muscle cell action potential involved in regulation of contraction	1	1872.4×	0.001	ATP2A2
regulation of cardiac muscle contraction by calcium ion signaling	1	1296.3×	0.001	ATP2A2
relaxation of cardiac muscle	1	1296.3×	0.001	ATP2A2
positive regulation of cardiac muscle cell apoptotic process	1	1203.7×	0.002	ATP2A2
cardiac muscle hypertrophy in response to stress	1	1053.2×	0.002	ATP2A2
regulation of the force of heart contraction	1	991.3×	0.002	ATP2A2
endoplasmic reticulum calcium ion homeostasis	1	842.6×	0.002	ATP2A2
regulation of cardiac conduction	1	842.6×	0.002	ATP2A2
positive regulation of heart rate	1	702.2×	0.002	ATP2A2
neuron cellular homeostasis	1	455.5×	0.003	ATP2A2
autophagosome assembly	1	224.7×	0.006	ATP2A2
epidermis development	1	210.7×	0.006	ATP2A2
calcium ion transmembrane transport	1	210.7×	0.006	ATP2A2
monoatomic ion transmembrane transport	1	208.1×	0.006	ATP2A2
response to endoplasmic reticulum stress	1	166.8×	0.007	ATP2A2
cellular response to oxidative stress	1	154.6×	0.007	ATP2A2
intracellular calcium ion homeostasis	1	145.3×	0.007	ATP2A2

Therapeutics

Drug target analysis

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

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
ATP2A2	1	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CURCUMIN	3	ATP2A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ATP2A2	19	Binding:19

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
CURCUMIN	3	ATP2A2

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	1	ATP2A2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
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.
NCT06614777	Not specified	RECRUITING	Characterization of the Cytokine Profile and the Microbiome in Darier’s Disease
NCT00001292	Not specified	COMPLETED	Study of Scaling Disorders and Other Inherited Skin Diseases
NCT00074685	Not specified	COMPLETED	National Registry for Ichthyosis and Related Disorders