Acne inversa, familial, 3

Summary

Acne inversa, familial, 3 (MONDO:0013398) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 246

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	acne inversa, familial, 3
Mondo ID	MONDO:0013398
OMIM	613737
UMLS	C3151038
MedGen	462388
Is cancer (heuristic)	no

Also known as: acne inversa, familial, 3 · acne inversa, familial, type 3 · ACNINV3 · familial acne inversa caused by mutation in PSEN1 · PSEN1 familial acne inversa

Data availability: 246 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › inflammatory disease › hidradenitis › hidradenitis suppurativa › familial acne inversa › acne inversa, familial, 3

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

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

246 retrieved; paginated sample, class counts are floors:

81 uncertain significance, 50 likely benign, 45 pathogenic, 32 conflicting classifications of pathogenicity, 16 pathogenic/likely pathogenic, 10 likely pathogenic, 7 benign, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1045636	NM_000021.4(PSEN1):c.667C>A (p.Gln223Lys)	PSEN1	Pathogenic	criteria provided, single submitter
1178342	NM_000021.4(PSEN1):c.1247T>C (p.Ile416Thr)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1450587	NM_000021.4(PSEN1):c.1129A>T (p.Arg377Trp)	PSEN1	Pathogenic	criteria provided, single submitter
1453682	NM_000021.4(PSEN1):c.750G>T (p.Leu250Phe)	PSEN1	Pathogenic	criteria provided, single submitter
1458372	NM_000021.4(PSEN1):c.838G>A (p.Glu280Lys)	PSEN1	Pathogenic	criteria provided, single submitter
1459049	NC_000014.8:g.(?73673074)(73673200_?)del	PSEN1	Pathogenic	criteria provided, single submitter
18123	NM_000021.4(PSEN1):c.436A>C (p.Met146Leu)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18124	NM_000021.4(PSEN1):c.488A>G (p.His163Arg)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18125	NM_000021.4(PSEN1):c.737C>A (p.Ala246Glu)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18127	NM_000021.4(PSEN1):c.1229G>A (p.Cys410Tyr)	PSEN1	Pathogenic	criteria provided, single submitter
18128	NM_000021.4(PSEN1):c.415A>G (p.Met139Val)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18131	NM_000021.4(PSEN1):c.839A>C (p.Glu280Ala)	PSEN1	Pathogenic	criteria provided, single submitter
18132	NM_000021.4(PSEN1):c.839A>G (p.Glu280Gly)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18136	NM_000021.4(PSEN1):c.1276G>C (p.Ala426Pro)	PSEN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18143	NM_000021.4(PSEN1):c.617G>C (p.Gly206Ala)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18148	NM_000021.4(PSEN1):c.811C>G (p.Leu271Val)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18152	NM_000021.4(PSEN1):c.833G>T (p.Arg278Ile)	PSEN1	Pathogenic	criteria provided, single submitter
18155	NM_000021.4(PSEN1):c.1292C>A (p.Ala431Glu)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18157	NM_000021.4(PSEN1):c.236C>T (p.Ala79Val)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1917985	NM_000021.4(PSEN1):c.845T>C (p.Leu282Pro)	PSEN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2028849	NM_000021.4(PSEN1):c.274T>A (p.Cys92Ser)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
21026	NM_000021.4(PSEN1):c.1175T>C (p.Leu392Pro)	PSEN1	Pathogenic	criteria provided, single submitter
21028	NM_000021.4(PSEN1):c.697A>G (p.Met233Val)	PSEN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137604	NM_000021.4(PSEN1):c.476A>T (p.Tyr159Phe)	PSEN1	Pathogenic	criteria provided, single submitter
2419054	NM_000021.4(PSEN1):c.766T>A (p.Tyr256Asn)	PSEN1	Pathogenic	criteria provided, single submitter
2925522	NM_000021.4(PSEN1):c.250A>G (p.Met84Val)	PSEN1	Pathogenic	criteria provided, single submitter
2925523	NM_000021.4(PSEN1):c.869-2A>G	PSEN1	Pathogenic	criteria provided, single submitter
29606	NM_000021.4(PSEN1):c.725del (p.Pro242fs)	PSEN1	Pathogenic	no assertion criteria provided
3759252	NM_000021.4(PSEN1):c.416T>A (p.Met139Lys)	PSEN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38297	NM_000021.4(PSEN1):c.806G>A (p.Arg269His)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 5 · 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
PSEN1	Limited	Autosomal dominant	acne inversa, familial, 3	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PSEN1	Orphanet:100069	Semantic dementia
PSEN1	Orphanet:100070	Progressive non-fluent aphasia
PSEN1	Orphanet:1020	Early-onset autosomal dominant Alzheimer disease
PSEN1	Orphanet:154	Familial isolated dilated cardiomyopathy
PSEN1	Orphanet:275864	Behavioral variant of frontotemporal dementia

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
PSEN1	HGNC:9508	ENSG00000080815	P49768	Presenilin-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PSEN1	Presenilin-1	Catalytic 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: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PSEN1	Protease	yes		Peptidase_A22A, Pept_A22A_PS1, Preselin/SPP

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
C1 segment of cervical spinal cord	1
corpus callosum	1
middle frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PSEN1	287	ubiquitous	marker	middle frontal gyrus, corpus callosum, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PSEN1	3,732

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSEN1	P49768	27

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
Noncanonical activation of NOTCH3	1	1427.5×	0.004	PSEN1
Regulated proteolysis of p75NTR	1	1038.2×	0.004	PSEN1
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	1038.2×	0.004	PSEN1
TGFBR3 PTM regulation	1	951.7×	0.004	PSEN1
NRIF signals cell death from the nucleus	1	713.8×	0.004	PSEN1
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	475.8×	0.004	PSEN1
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	439.2×	0.004	PSEN1
Activated NOTCH1 Transmits Signal to the Nucleus	1	356.9×	0.004	PSEN1
Nuclear signaling by ERBB4	1	346.1×	0.004	PSEN1
EPH-ephrin mediated repulsion of cells	1	219.6×	0.006	PSEN1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	196.9×	0.006	PSEN1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	196.9×	0.006	PSEN1
Degradation of the extracellular matrix	1	117.7×	0.009	PSEN1
Neutrophil degranulation	1	23.1×	0.043	PSEN1

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 L-glutamate import across plasma membrane	1	8426.0×	0.003	PSEN1
Cajal-Retzius cell differentiation	1	8426.0×	0.003	PSEN1
smooth endoplasmic reticulum calcium ion homeostasis	1	8426.0×	0.003	PSEN1
protein catabolic process at postsynapse	1	5617.3×	0.003	PSEN1
astrocyte activation involved in immune response	1	4213.0×	0.003	PSEN1
obsolete synaptic vesicle targeting	1	4213.0×	0.003	PSEN1
obsolete sequestering of calcium ion	1	3370.4×	0.003	PSEN1
positive regulation of amyloid fibril formation	1	3370.4×	0.003	PSEN1
positive regulation of coagulation	1	2808.7×	0.003	PSEN1
Notch receptor processing	1	1872.4×	0.003	PSEN1
amyloid-beta formation	1	1872.4×	0.003	PSEN1
L-glutamate import across plasma membrane	1	1872.4×	0.003	PSEN1
choline transport	1	1532.0×	0.003	PSEN1
cerebral cortex cell migration	1	1532.0×	0.003	PSEN1
locomotion	1	1532.0×	0.003	PSEN1
skin morphogenesis	1	1404.3×	0.003	PSEN1
amyloid precursor protein metabolic process	1	1296.3×	0.003	PSEN1
negative regulation of axonogenesis	1	1296.3×	0.003	PSEN1
regulation of resting membrane potential	1	1296.3×	0.003	PSEN1
mitochondrial transport	1	1203.7×	0.003	PSEN1
amyloid precursor protein catabolic process	1	1203.7×	0.003	PSEN1
positive regulation of receptor recycling	1	1123.5×	0.003	PSEN1
regulation of synaptic vesicle cycle	1	1123.5×	0.003	PSEN1
neuron projection maintenance	1	1123.5×	0.003	PSEN1
astrocyte activation	1	991.3×	0.003	PSEN1
neural retina development	1	936.2×	0.003	PSEN1
myeloid dendritic cell differentiation	1	936.2×	0.003	PSEN1
endoplasmic reticulum calcium ion homeostasis	1	842.6×	0.003	PSEN1
negative regulation of ubiquitin-dependent protein catabolic process	1	842.6×	0.003	PSEN1
dorsal/ventral neural tube patterning	1	802.5×	0.003	PSEN1

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
PSEN1	NIROGACESTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSEN1	8	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIROGACESTAT	4	PSEN1
TARENFLURBIL	3	PSEN1
SEMAGACESTAT	3	PSEN1
AVAGACESTAT	2	PSEN1
RG-4733	2	PSEN1
BEGACESTAT	2	PSEN1
E-2212	1	PSEN1
MK-0752	1	PSEN1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PSEN1	557	Binding:538, 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
PSEN1	557

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	PSEN1
TARENFLURBIL	3	PSEN1
SEMAGACESTAT	3	PSEN1
AVAGACESTAT	2	PSEN1
RG-4733	2	PSEN1
BEGACESTAT	2	PSEN1
E-2212	1	PSEN1
MK-0752	1	PSEN1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PSEN1
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.