Acrokeratosis verruciformis

Summary

Acrokeratosis verruciformis (MONDO:0007048) is a disease caused by ATP2A2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: ATP2A2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 26
• Phenotypes (HPO): 12

Clinical features

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0000962	Hyperkeratosis	Very frequent (80-99%)
HP:0008404	Nail dystrophy	Very frequent (80-99%)
HP:0025092	Epidermal acanthosis	Very frequent (80-99%)
HP:0025114	Hypergranulosis	Very frequent (80-99%)
HP:0025512	Skin-colored papule	Very frequent (80-99%)
HP:0007530	Punctate palmoplantar hyperkeratosis	Frequent (30-79%)
HP:0200035	Skin plaque	Frequent (30-79%)
HP:0200043	Verrucae	Frequent (30-79%)
HP:0001820	Leukonychia	Frequent (30-79%)
HP:0001798	Anonychia	Occasional (5-29%)
HP:0001036	Parakeratosis	Excluded (0%)
HP:0100792	Acantholysis	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	acrokeratosis verruciformis
Mondo ID	MONDO:0007048
EFO	EFO:1000666
OMIM	101900
Orphanet	79151
DOID	DOID:0050606
NCIT	C27519
SNOMED CT	400085009
UMLS	C0265971
MedGen	75589
GARD	0016707
MedDRA	10069445
Is cancer (heuristic)	no

Also known as: acrokeratosis verruciformis · acrokeratosis verruciformis of Hopf · AKV · AKV of Hopf · Hopf disease

Data availability: 26 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › keratosis › acrokeratosis verruciformis

Related subtypes (8): keratosis follicularis spinulosa decalvans, acquired keratosis, cholesteatoma, palmoplantar keratosis, porokeratosis, hereditary papulotranslucent acrokeratoderma, seborrheic keratosis, trichostasis spinulosa

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:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
17799	NM_170665.4(ATP2A2):c.1805C>T (p.Pro602Leu)	ATP2A2	Pathogenic	criteria provided, multiple submitters, no conflicts
29610	NM_170665.4(ATP2A2):c.2093C>T (p.Ala698Val)	ATP2A2	Pathogenic	no assertion criteria provided
4796542	NM_170665.4(ATP2A2):c.2788_2790dup (p.Ile930_Trp931insIle)	ATP2A2	Likely pathogenic	criteria provided, single submitter
931158	NM_170665.4(ATP2A2):c.136+21_136+22del	ATP2A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1342440	NM_170665.4(ATP2A2):c.2030G>C (p.Arg677Pro)	ATP2A2	Uncertain significance	criteria provided, single submitter
3574249	NM_170665.4(ATP2A2):c.2168C>T (p.Thr723Ile)	ATP2A2	Uncertain significance	criteria provided, single submitter
930659	NM_170665.4(ATP2A2):c.688A>G (p.Thr230Ala)	ATP2A2	Uncertain significance	criteria provided, single submitter
307158	NM_170665.4(ATP2A2):c.-10C>G	ATP2A2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
307159	NM_170665.4(ATP2A2):c.81A>G (p.Glu27=)	ATP2A2	Benign	criteria provided, multiple submitters, no conflicts
307165	NM_170665.4(ATP2A2):c.327A>G (p.Glu109=)	ATP2A2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
307170	NM_170665.4(ATP2A2):c.1167T>C (p.Tyr389=)	ATP2A2	Benign	criteria provided, multiple submitters, no conflicts
307171	NM_170665.4(ATP2A2):c.1323A>G (p.Thr441=)	ATP2A2	Benign	criteria provided, multiple submitters, no conflicts
307172	NM_170665.4(ATP2A2):c.1420-8C>G	ATP2A2	Benign	criteria provided, multiple submitters, no conflicts
307177	NM_170665.4(ATP2A2):c.2058C>T (p.Ile686=)	ATP2A2	Benign	criteria provided, multiple submitters, no conflicts
307178	NM_170665.4(ATP2A2):c.2172G>A (p.Ala724=)	ATP2A2	Benign	criteria provided, multiple submitters, no conflicts
307180	NM_170665.4(ATP2A2):c.2319-12G>A	ATP2A2	Benign	criteria provided, multiple submitters, no conflicts
307184	NM_170665.4(ATP2A2):c.2742-6C>T	ATP2A2	Benign	criteria provided, multiple submitters, no conflicts
307185	NM_170665.4(ATP2A2):c.2860-10TG[2]	ATP2A2	Benign	criteria provided, multiple submitters, no conflicts
3338254	NM_170665.4(ATP2A2):c.1997G>A (p.Arg666Gln)	ATP2A2	Benign	criteria provided, single submitter
377532	NM_170665.4(ATP2A2):c.220-18G>A	ATP2A2	Benign	criteria provided, multiple submitters, no conflicts
379690	NM_170665.4(ATP2A2):c.1096-16C>T	ATP2A2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
446883	NM_170665.4(ATP2A2):c.2925C>T (p.Pro975=)	ATP2A2	Benign	criteria provided, multiple submitters, no conflicts
585465	NM_170665.4(ATP2A2):c.545-7C>T	ATP2A2	Benign	criteria provided, multiple submitters, no conflicts
776751	NM_170665.4(ATP2A2):c.2202G>A (p.Leu734=)	ATP2A2	Benign	criteria provided, multiple submitters, no conflicts
804551	NM_170665.4(ATP2A2):c.1287+3A>G	ATP2A2	Benign	criteria provided, multiple submitters, no conflicts
307183	NM_170665.4(ATP2A2):c.2628A>G (p.Lys876=)	LOC126861638	Benign	criteria provided, multiple submitters, no conflicts

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	acrokeratosis verruciformis	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: 0.