Acne inversa, familial, 1

Summary

Acne inversa, familial, 1 (MONDO:0007728) is a disease caused by NCSTN (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: NCSTN (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	acne inversa, familial, 1
Mondo ID	MONDO:0007728
OMIM	142690
UMLS	C4551962
MedGen	1631104
Is cancer (heuristic)	no

Also known as: acne inversa, familial, 1 · acne inversa, familial, type 1 · ACNINV1 · familial acne inversa caused by mutation in NCSTN · NCSTN familial acne inversa

Data availability: 22 ClinVar variants · 3 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, 1

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

22 retrieved; paginated sample, class counts are floors:

8 pathogenic, 5 uncertain significance, 3 conflicting classifications of pathogenicity, 3 likely pathogenic, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1179000	NM_015331.3(NCSTN):c.97G>A (p.Gly33Arg)	NCSTN	Pathogenic	no assertion criteria provided
1179001	NM_015331.3(NCSTN):c.1285C>T (p.Arg429Ter)	NCSTN	Pathogenic	no assertion criteria provided
225419	NM_015331.3(NCSTN):c.1300C>T (p.Arg434Ter)	NCSTN	Pathogenic	criteria provided, single submitter
2430258	NM_015331.3(NCSTN):c.1101_1101+17delinsTGTCCA	NCSTN	Pathogenic	criteria provided, single submitter
30452	NM_015331.3(NCSTN):c.1752del (p.Glu584fs)	NCSTN	Pathogenic	no assertion criteria provided
30453	NM_015331.3(NCSTN):c.1551+1G>A	NCSTN	Pathogenic	no assertion criteria provided
30454	NM_015331.3(NCSTN):c.349C>T (p.Arg117Ter)	NCSTN	Pathogenic	criteria provided, single submitter
446481	NM_015331.3(NCSTN):c.1101+1G>A	NCSTN	Pathogenic	no assertion criteria provided
3377655	NM_015331.3(NCSTN):c.278dup (p.Tyr94fs)	NCSTN	Likely pathogenic	criteria provided, single submitter
4082100	NM_015331.3(NCSTN):c.579del (p.Lys193fs)	NCSTN	Likely pathogenic	criteria provided, single submitter
4292514	NM_015331.3(NCSTN):c.1654del (p.Gln552fs)	NCSTN	Likely pathogenic	criteria provided, single submitter
1165454	NM_015331.3(NCSTN):c.996+7G>A	NCSTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1523300	NM_015331.3(NCSTN):c.1102-10C>A	NCSTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
559854	NM_015331.3(NCSTN):c.944C>T (p.Ala315Val)	NCSTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1520214	NM_015331.3(NCSTN):c.1070A>G (p.Glu357Gly)	NCSTN	Uncertain significance	criteria provided, multiple submitters, no conflicts
1935945	NM_015331.3(NCSTN):c.915G>T (p.Gln305His)	NCSTN	Uncertain significance	criteria provided, multiple submitters, no conflicts
2164046	NM_015331.3(NCSTN):c.56G>A (p.Arg19His)	NCSTN	Uncertain significance	criteria provided, multiple submitters, no conflicts
2500064	NM_015331.3(NCSTN):c.1179+6C>G	NCSTN	Uncertain significance	criteria provided, single submitter
4072299	NM_015331.3(NCSTN):c.1179+59C>T	NCSTN	Uncertain significance	criteria provided, single submitter
1167236	NM_015331.3(NCSTN):c.1101+13T>C	NCSTN	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1170163	NM_015331.3(NCSTN):c.1249A>T (p.Asn417Tyr)	NCSTN	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1606190	NM_015331.3(NCSTN):c.437-12C>G	NCSTN	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
NCSTN	Strong	Autosomal dominant	acne inversa, familial, 1	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NCSTN	Orphanet:289478	PASH syndrome

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
NCSTN	HGNC:17091	ENSG00000162736	Q92542	Nicastrin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NCSTN	Nicastrin	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)
NCSTN	Other/Unknown	no		Nicastrin, Ncstrn_small

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
monocyte	1
mononuclear cell	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NCSTN	285	ubiquitous	marker	stromal cell of endometrium, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NCSTN	1,976

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NCSTN	Q92542	30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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×	0.004	NCSTN
Regulated proteolysis of p75NTR	1	1038.2×	0.004	NCSTN
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	1038.2×	0.004	NCSTN
TGFBR3 PTM regulation	1	951.7×	0.004	NCSTN
NRIF signals cell death from the nucleus	1	713.8×	0.004	NCSTN
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	475.8×	0.005	NCSTN
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	439.2×	0.005	NCSTN
Activated NOTCH1 Transmits Signal to the Nucleus	1	356.9×	0.005	NCSTN
Nuclear signaling by ERBB4	1	346.1×	0.005	NCSTN
EPH-ephrin mediated repulsion of cells	1	219.6×	0.006	NCSTN
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	196.9×	0.006	NCSTN
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	196.9×	0.006	NCSTN
Degradation of the extracellular matrix	1	117.7×	0.010	NCSTN
Amyloid fiber formation	1	102.9×	0.010	NCSTN
Neutrophil degranulation	1	23.1×	0.043	NCSTN

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
amyloid precursor protein biosynthetic process	1	16852.0×	0.001	NCSTN
short-term synaptic potentiation	1	5617.3×	0.002	NCSTN
positive regulation of amyloid precursor protein biosynthetic process	1	3370.4×	0.002	NCSTN
myeloid cell homeostasis	1	2106.5×	0.002	NCSTN
G protein-coupled dopamine receptor signaling pathway	1	1872.4×	0.002	NCSTN
Notch receptor processing	1	1872.4×	0.002	NCSTN
amyloid-beta formation	1	1872.4×	0.002	NCSTN
regulation of long-term synaptic potentiation	1	1532.0×	0.002	NCSTN
amyloid precursor protein metabolic process	1	1296.3×	0.002	NCSTN
membrane protein intracellular domain proteolysis	1	1203.7×	0.002	NCSTN
amyloid precursor protein catabolic process	1	1203.7×	0.002	NCSTN
central nervous system myelination	1	991.3×	0.002	NCSTN
glutamate receptor signaling pathway	1	936.2×	0.002	NCSTN
membrane protein ectodomain proteolysis	1	648.1×	0.003	NCSTN
adult behavior	1	468.1×	0.003	NCSTN
T cell proliferation	1	383.0×	0.004	NCSTN
cerebellum development	1	358.6×	0.004	NCSTN
epithelial cell proliferation	1	312.1×	0.004	NCSTN
learning or memory	1	240.7×	0.005	NCSTN
cellular response to calcium ion	1	200.6×	0.006	NCSTN
neuron apoptotic process	1	185.2×	0.006	NCSTN
protein processing	1	170.2×	0.006	NCSTN
Notch signaling pathway	1	141.6×	0.007	NCSTN
proteolysis	1	34.2×	0.029	NCSTN

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
NCSTN	NIROGACESTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NCSTN	8	4

Drugs targeting cohort genes (top 30)

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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NCSTN	480	Binding:461, Functional:12, 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
NCSTN	480

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	NCSTN
TARENFLURBIL	3	NCSTN
SEMAGACESTAT	3	NCSTN
AVAGACESTAT	2	NCSTN
RG-4733	2	NCSTN
BEGACESTAT	2	NCSTN
E-2212	1	NCSTN
MK-0752	1	NCSTN

Druggability pyramid

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

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