Acne inversa, familial, 2

Summary

Acne inversa, familial, 2 (MONDO:0013397) is a disease caused by PSENEN (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PSENEN (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	acne inversa, familial, 2
Mondo ID	MONDO:0013397
OMIM	613736
UMLS	C3151037
MedGen	462387
Is cancer (heuristic)	no

Also known as: acne inversa, familial, 2 · acne inversa, familial, type 2 · ACNINV2 · familial acne inversa caused by mutation in PSENEN · PSENEN familial acne inversa

Data availability: 9 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › inflammatory disease › hidradenitis › hidradenitis suppurativa › familial acne inversa › acne inversa, familial, 2

Related subtypes (2): acne inversa, familial, 1, acne inversa, familial, 3

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

9 retrieved; paginated sample, class counts are floors:

7 pathogenic, 1 uncertain significance, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
30681	NM_172341.4(PSENEN):c.66del	PSENEN	Pathogenic	no assertion criteria provided
30682	NM_172341.4(PSENEN):c.279del (p.Phe94fs)	PSENEN	Pathogenic	no assertion criteria provided
446482	NC_000019.10:g.35746423dup	PSENEN	Pathogenic	no assertion criteria provided
446483	NM_172341.4(PSENEN):c.35T>A (p.Leu12Ter)	PSENEN	Pathogenic	no assertion criteria provided
446484	NM_172341.4(PSENEN):c.194T>G (p.Leu65Arg)	PSENEN	Pathogenic	no assertion criteria provided
446485	NM_172341.4(PSENEN):c.167-2A>G	PSENEN	Pathogenic	no assertion criteria provided
446486	NM_172341.4(PSENEN):c.62-1G>C	PSENEN	Pathogenic	no assertion criteria provided
2585266	NM_172341.4(PSENEN):c.185_200del (p.Val62fs)	PSENEN	Uncertain significance	criteria provided, single submitter
518298	NM_172341.4(PSENEN):c.61+17G>C	PSENEN	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
PSENEN	Strong	Autosomal dominant	acne inversa, familial, 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PSENEN	Orphanet:79145	Dowling-Degos 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
PSENEN	HGNC:30100	ENSG00000205155	Q9NZ42	Gamma-secretase subunit PEN-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PSENEN	Gamma-secretase subunit PEN-2	Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein).

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)
PSENEN	Other/Unknown	no		Gamma_Secretase_Asp_P_PEN2

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
olfactory segment of nasal mucosa	1
right testis	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PSENEN	140	ubiquitous	marker	right uterine tube, olfactory segment of nasal mucosa, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PSENEN	1,088

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSENEN	Q9NZ42	27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Noncanonical activation of NOTCH3	1	1427.5×	0.003	PSENEN
Regulated proteolysis of p75NTR	1	1038.2×	0.003	PSENEN
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	1038.2×	0.003	PSENEN
TGFBR3 PTM regulation	1	951.7×	0.003	PSENEN
NRIF signals cell death from the nucleus	1	713.8×	0.004	PSENEN
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	475.8×	0.004	PSENEN
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	439.2×	0.004	PSENEN
Activated NOTCH1 Transmits Signal to the Nucleus	1	356.9×	0.004	PSENEN
Nuclear signaling by ERBB4	1	346.1×	0.004	PSENEN
EPH-ephrin mediated repulsion of cells	1	219.6×	0.006	PSENEN
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	196.9×	0.006	PSENEN
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	196.9×	0.006	PSENEN
Amyloid fiber formation	1	102.9×	0.010	PSENEN

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
positive regulation of endopeptidase activity	1	5617.3×	0.001	PSENEN
Notch receptor processing	1	1872.4×	0.001	PSENEN
amyloid-beta formation	1	1872.4×	0.001	PSENEN
amyloid precursor protein metabolic process	1	1296.3×	0.001	PSENEN
membrane protein intracellular domain proteolysis	1	1203.7×	0.001	PSENEN
amyloid precursor protein catabolic process	1	1203.7×	0.001	PSENEN
membrane protein ectodomain proteolysis	1	648.1×	0.002	PSENEN
protein processing	1	170.2×	0.007	PSENEN
Notch signaling pathway	1	141.6×	0.007	PSENEN

Therapeutics

Drug target analysis

Approved (phase 4): 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PSENEN	NIROGACESTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSENEN	8	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIROGACESTAT	4	PSENEN
TARENFLURBIL	3	PSENEN
SEMAGACESTAT	3	PSENEN
AVAGACESTAT	2	PSENEN
RG-4733	2	PSENEN
BEGACESTAT	2	PSENEN
E-2212	1	PSENEN
MK-0752	1	PSENEN

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PSENEN	487	Binding:464, Functional:16, ADMET:6, Unclassified:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PSENEN	487

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

8 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)
NIROGACESTAT	4	PSENEN
TARENFLURBIL	3	PSENEN
SEMAGACESTAT	3	PSENEN
AVAGACESTAT	2	PSENEN
RG-4733	2	PSENEN
BEGACESTAT	2	PSENEN
E-2212	1	PSENEN
MK-0752	1	PSENEN

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PSENEN
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	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.