Familial focal epilepsy with variable foci

Summary

Familial focal epilepsy with variable foci (MONDO:0020310) is a disease with 4 cohort genes. The dominant Reactome pathway is Amino acids regulate mTORC1 (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 4
• ClinVar variants: 2,138
• Phenotypes (HPO): 26

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		76	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0007359	Focal-onset seizure	Very frequent (80-99%)
HP:0011185	EEG with focal epileptiform discharges	Very frequent (80-99%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0025373	Interictal EEG abnormality	Frequent (30-79%)
HP:0031951	Nocturnal seizures	Frequent (30-79%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000980	Pallor	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0002349	Focal aware seizure	Occasional (5-29%)
HP:0002367	Visual hallucinations	Occasional (5-29%)
HP:0002384	Focal impaired awareness seizure	Occasional (5-29%)
HP:0002427	Motor aphasia	Occasional (5-29%)
HP:0003401	Paresthesia	Occasional (5-29%)
HP:0008765	Auditory hallucinations	Occasional (5-29%)
HP:0010841	Multifocal epileptiform discharges	Occasional (5-29%)
HP:0012005	Deja vu	Occasional (5-29%)
HP:0012469	Infantile spasms	Occasional (5-29%)
HP:0012531	Pain	Occasional (5-29%)
HP:0031284	Flushing	Occasional (5-29%)
HP:0032046	Focal cortical dysplasia	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)
HP:0002126	Polymicrogyria	Very rare (<1-4%)
HP:0002521	Hypsarrhythmia	Very rare (<1-4%)
HP:0007206	Hemimegalencephaly	Very rare (<1-4%)
HP:0011171	Simple febrile seizures	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial focal epilepsy with variable foci
Mondo ID	MONDO:0020310
MeSH	C565785
OMIM	604364
Orphanet	98820
DOID	DOID:0081420
ICD-11	855404450
SNOMED CT	764522009
UMLS	C1858477
MedGen	348951
GARD	0013295
Is cancer (heuristic)	no

Also known as: epilepsy, familial focal, with variable foci · familial focal epilepsy with variable foci · familial partial epilepsy with variable foci · FFEVF

Data availability: 2,138 ClinVar variants · 4 GenCC gene-disease records · 6 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › focal epilepsy › familial partial epilepsy › familial focal epilepsy with variable foci

Related subtypes (6): familial sleep-related hypermotor epilepsy, temporal lobe epilepsy, self-limited epilepsy with centrotemporal spikes, autosomal dominant epilepsy with auditory features, generalized epilepsy-paroxysmal dyskinesia syndrome, mesial temporal lobe epilepsy with hippocampal sclerosis

Subtypes (4): epilepsy, familial focal, with variable foci 2, epilepsy, familial focal, with variable foci 3, epilepsy, familial focal, with variable foci 1, epilepsy, familial focal, with variable foci 4

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

600 retrieved; paginated sample, class counts are floors:

262 uncertain significance, 222 likely benign, 68 pathogenic, 16 likely pathogenic, 13 conflicting classifications of pathogenicity, 12 benign, 4 pathogenic/likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068966	NM_001242896.3(DEPDC5):c.800G>A (p.Trp267Ter)	DEPDC5	Pathogenic	criteria provided, single submitter
1069166	NC_000022.10:g.(?32160941)(32161066_?)del	DEPDC5	Pathogenic	criteria provided, single submitter
1069167	NC_000022.10:g.(?32179873)(32179991_?)del	DEPDC5	Pathogenic	criteria provided, single submitter
1069168	NC_000022.10:g.(?32180780)(32302503_?)del	DEPDC5	Pathogenic	criteria provided, single submitter
1069222	NM_001242896.3(DEPDC5):c.2275_2281del (p.Tyr759fs)	DEPDC5	Pathogenic	criteria provided, single submitter
1069249	NM_001242896.3(DEPDC5):c.158del (p.Leu53fs)	DEPDC5	Pathogenic	criteria provided, single submitter
1069270	NM_001242896.3(DEPDC5):c.208_209del (p.Asp70fs)	DEPDC5	Pathogenic	criteria provided, single submitter
1069325	NM_001242896.3(DEPDC5):c.2196dup (p.Val733fs)	DEPDC5	Pathogenic	criteria provided, single submitter
1069373	NM_001242896.3(DEPDC5):c.2548dup (p.Asp850fs)	DEPDC5	Pathogenic	criteria provided, single submitter
1069404	NM_001242896.3(DEPDC5):c.3205C>T (p.Gln1069Ter)	DEPDC5	Pathogenic	criteria provided, single submitter
1070245	NM_001242896.3(DEPDC5):c.4290del (p.Tyr1431fs)	DEPDC5	Pathogenic	criteria provided, single submitter
1070712	NM_001242896.3(DEPDC5):c.4671_4672del (p.Trp1558fs)	DEPDC5	Pathogenic	criteria provided, single submitter
1070820	NM_001242896.3(DEPDC5):c.2958_2959insTTTTTTTTTTTTTTTTNNNNNNNNNNTTTTTTTTTTTTTTTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCCAGGCTGGAGTGCAGTGGCGGGATCTCGGCTCACTGCAAGCTCCGCCTCCTGGATGGTTTT (p.Val987delinsPhePhePhePhePheXaaXaaXaaXaaPhePhePhePhePhePhePhePhePheTer)	DEPDC5	Pathogenic	criteria provided, single submitter
1071232	NM_001242896.3(DEPDC5):c.3578del (p.Leu1193fs)	DEPDC5	Pathogenic	criteria provided, single submitter
1071236	NM_001242896.3(DEPDC5):c.862del (p.Glu288fs)	DEPDC5	Pathogenic	criteria provided, single submitter
1071273	NC_000022.10:g.(?32188019)(32194642_?)del	DEPDC5	Pathogenic	criteria provided, single submitter
1071274	NC_000022.10:g.(?32205577)(32206647_?)del	DEPDC5	Pathogenic	criteria provided, single submitter
1071275	NC_000022.10:g.(?32150888)(32188823_?)del	DEPDC5	Pathogenic	criteria provided, single submitter
1071348	NM_001242896.3(DEPDC5):c.2898C>A (p.Cys966Ter)	DEPDC5	Pathogenic	criteria provided, single submitter
1072903	NM_001242896.3(DEPDC5):c.2094dup (p.Ser699fs)	DEPDC5	Pathogenic	criteria provided, single submitter
1073135	NM_001242896.3(DEPDC5):c.3449_3450del (p.Glu1150fs)	DEPDC5	Pathogenic	criteria provided, single submitter
1073159	NM_001242896.3(DEPDC5):c.280-2A>G	DEPDC5	Pathogenic	criteria provided, single submitter
1073184	NC_000022.10:g.(?32150888)(32162674_?)del	DEPDC5	Pathogenic	criteria provided, single submitter
1073185	NC_000022.10:g.(?32150888)(32164869_?)del	DEPDC5	Pathogenic	criteria provided, single submitter
1073186	NC_000022.10:g.(?32301960)(32302483_?)del	DEPDC5	Pathogenic	criteria provided, single submitter
1073187	NC_000022.10:g.(?32174065)(32180881_?)del	DEPDC5	Pathogenic	criteria provided, single submitter
1073664	NM_001242896.3(DEPDC5):c.247C>T (p.Gln83Ter)	DEPDC5	Pathogenic	criteria provided, single submitter
1073683	NM_001242896.3(DEPDC5):c.305dup (p.Leu102fs)	DEPDC5	Pathogenic	criteria provided, single submitter
1074181	NM_001242896.3(DEPDC5):c.2489_2511del (p.Leu830fs)	DEPDC5	Pathogenic	criteria provided, single submitter
1074536	NM_001242896.3(DEPDC5):c.176dup (p.Glu60fs)	DEPDC5	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 32 · Orphanet: 12 · 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
DEPDC5	Definitive	Autosomal dominant	epilepsy, familial focal, with variable foci 1	11
NPRL2	Strong	Autosomal dominant	epilepsy, familial focal, with variable foci 2	17
NPRL3	Strong	Autosomal dominant	epilepsy, familial focal, with variable foci 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DEPDC5	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
DEPDC5	Orphanet:98784	Sleep-related hypermotor epilepsy
DEPDC5	Orphanet:98820	Familial focal epilepsy with variable foci
NPRL2	Orphanet:98820	Familial focal epilepsy with variable foci
NPRL3	Orphanet:98820	Familial focal epilepsy with variable foci
APP	Orphanet:100006	ABeta amyloidosis, Dutch type
APP	Orphanet:1020	Early-onset autosomal dominant Alzheimer disease
APP	Orphanet:324703	ABetaL34V amyloidosis
APP	Orphanet:324708	ABeta amyloidosis, Iowa type
APP	Orphanet:324713	ABeta amyloidosis, Italian type
APP	Orphanet:324718	ABetaA21G amyloidosis
APP	Orphanet:324723	ABeta amyloidosis, Arctic type

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DEPDC5	HGNC:18423	ENSG00000100150	O75140	GATOR1 complex protein DEPDC5	gencc,clinvar
NPRL2	HGNC:24969	ENSG00000114388	Q8WTW4	GATOR1 complex protein NPRL2	gencc,clinvar
NPRL3	HGNC:14124	ENSG00000103148	Q12980	GATOR1 complex protein NPRL3	gencc
APP	HGNC:620	ENSG00000142192	P05067	Amyloid-beta precursor protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DEPDC5	GATOR1 complex protein DEPDC5	As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
NPRL2	GATOR1 complex protein NPRL2	Catalytic component of the GATOR1 complex, a multiprotein complex that functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
NPRL3	GATOR1 complex protein NPRL3	As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
APP	Amyloid-beta precursor protein	Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DEPDC5	Other/Unknown	no		DEP_dom, IML1, WH-like_DNA-bd_sf
NPRL2	Other/Unknown	no		NPR2-like
NPRL3	Other/Unknown	no		Npr3, HTH_NPRL3
APP	Other/Unknown	no		Kunitz_BPTI, Amyloid_glyco_extra, Amyloid_glyco

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
frontal pole	1
middle frontal gyrus	1
paraflocculus	1
cerebellar hemisphere	1
granulocyte	1
right hemisphere of cerebellum	1
blood	1
hindlimb stylopod muscle	1
right uterine tube	1
Brodmann (1909) area 9	1
prefrontal cortex	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DEPDC5	236	ubiquitous	marker	paraflocculus, frontal pole, middle frontal gyrus
NPRL2	285	ubiquitous	marker	granulocyte, right hemisphere of cerebellum, cerebellar hemisphere
NPRL3	276	ubiquitous	marker	blood, hindlimb stylopod muscle, right uterine tube
APP	295	ubiquitous	marker	prefrontal cortex, renal medulla, Brodmann (1909) area 9

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APP	11,686
NPRL3	1,511
DEPDC5	1,273
NPRL2	1,222

Intra-cohort edges

A	B	Sources
DEPDC5	NPRL2	biogrid_interaction, intact, string_interaction
DEPDC5	NPRL3	biogrid_interaction, intact, string_interaction
NPRL2	NPRL3	biogrid_interaction, intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APP	P05067	256
DEPDC5	O75140	11
NPRL2	Q8WTW4	10
NPRL3	Q12980	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 70. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Amino acids regulate mTORC1	3	150.3×	3e-05	DEPDC5, NPRL2, NPRL3
Aggregated β-amyloid induces FXII autocatalysis	1	1427.5×	0.025	APP
Aggregated β-amyloid interacts with fibrinogen	1	713.8×	0.033	APP
Formyl peptide receptors bind formyl peptides and many other ligands	1	356.9×	0.040	APP
Inflammasomes	1	285.5×	0.040	APP
Cell recruitment (pro-inflammatory response)	1	285.5×	0.040	APP
Neurodegenerative Diseases	1	219.6×	0.040	APP
Defective Intrinsic Pathway for Apoptosis	1	190.3×	0.040	APP
Advanced glycosylation endproduct receptor signaling	1	178.4×	0.040	APP
The NLRP3 inflammasome	1	167.9×	0.040	APP
Diseases of programmed cell death	1	158.6×	0.040	APP
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	129.8×	0.044	APP
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	1	119.0×	0.044	APP
TRAF6 mediated NF-kB activation	1	114.2×	0.044	APP
Purinergic signaling in leishmaniasis infection	1	105.7×	0.044	APP
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1	89.2×	0.044	APP
Lysosome Vesicle Biogenesis	1	81.6×	0.044	APP
TAK1-dependent IKK and NF-kappa-B activation	1	75.1×	0.044	APP
Interleukin-1 family signaling	1	68.0×	0.044	APP
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1	63.4×	0.044	APP
trans-Golgi Network Vesicle Budding	1	63.4×	0.044	APP
Regulation of clotting cascade	1	58.3×	0.044	APP
Toll Like Receptor 10 (TLR10) Cascade	1	53.9×	0.044	APP
Toll Like Receptor 5 (TLR5) Cascade	1	53.9×	0.044	APP
MyD88 cascade initiated on plasma membrane	1	51.0×	0.044	APP
Toll Like Receptor 3 (TLR3) Cascade	1	48.4×	0.044	APP
TRIF (TICAM1)-mediated TLR4 signaling	1	47.6×	0.044	APP
Protein localization	1	47.6×	0.044	APP
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1	47.6×	0.044	APP
MyD88 dependent cascade initiated on endosome	1	47.6×	0.044	APP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of TORC1 signaling	3	243.1×	5e-06	DEPDC5, NPRL2, NPRL3
cellular response to amino acid starvation	3	238.5×	5e-06	DEPDC5, NPRL2, NPRL3
positive regulation of autophagy	3	156.0×	1e-05	DEPDC5, NPRL2, NPRL3
collateral sprouting in absence of injury	1	1404.3×	0.007	APP
astrocyte activation involved in immune response	1	1053.2×	0.007	APP
axo-dendritic transport	1	1053.2×	0.007	APP
microglia development	1	1053.2×	0.007	APP
negative regulation of kinase activity	1	1053.2×	0.007	NPRL2
cellular response to norepinephrine stimulus	1	1053.2×	0.007	APP
regulation of spontaneous synaptic transmission	1	1053.2×	0.007	APP
axon midline choice point recognition	1	842.6×	0.007	APP
swimming behavior	1	842.6×	0.007	APP
hippocampal neuron apoptotic process	1	842.6×	0.007	APP
positive regulation of amyloid fibril formation	1	842.6×	0.007	APP
mating behavior	1	702.2×	0.007	APP
regulation of synapse structure or activity	1	702.2×	0.007	APP
response to insulin-like growth factor stimulus	1	702.2×	0.007	APP
cellular response to manganese ion	1	601.9×	0.007	APP
NMDA selective glutamate receptor signaling pathway	1	601.9×	0.007	APP
modulation of excitatory postsynaptic potential	1	526.6×	0.008	APP
ionotropic glutamate receptor signaling pathway	1	324.1×	0.011	APP
negative regulation of long-term synaptic potentiation	1	324.1×	0.011	APP
neuron remodeling	1	300.9×	0.011	APP
neuron projection maintenance	1	280.9×	0.011	APP
astrocyte activation	1	247.8×	0.011	APP
regulation of long-term neuronal synaptic plasticity	1	247.8×	0.011	APP
positive regulation of protein metabolic process	1	247.8×	0.011	APP
intracellular copper ion homeostasis	1	234.1×	0.011	APP
response to lead ion	1	234.1×	0.011	APP
regulation of Wnt signaling pathway	1	221.7×	0.011	APP

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
APP	FLORBETAPIR F 18

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APP	40	4
DEPDC5	0	0
NPRL2	0	0
NPRL3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FLORBETAPIR F 18	4	APP
FLORBETAPIR	4	APP
METHYLENE BLUE CATION	4	APP
FLUTEMETAMOL F 18	4	APP
TRETINOIN	4	APP
METHYLENE BLUE ANHYDROUS	4	APP
CLIOQUINOL	4	APP
DONEPEZIL	4	APP
FLORBETABEN F18	4	APP
NIACIN	4	APP
FLUTEMETAMOL	4	APP
GENTIAN VIOLET	4	APP
AMODIAQUINE	4	APP
CARVEDILOL	4	APP
CHLOROQUINE	4	APP
TACRINE	4	APP
RETINOL	4	APP
CURCUMIN	3	APP
CAFFEIC ACID	3	APP
TRAMIPROSATE	3	APP
RESVERATROL	3	APP
FLUTAFURANOL	3	APP
EPIGALOCATECHIN GALLATE	3	APP
LANABECESTAT	3	APP
QUERCETIN	3	APP
EDETIC ACID	3	APP
PARAROSANILINE	2	APP
LUTEOLIN	2	APP
PITTSBURGH COMPOUND B	2	APP
AFTOBETIN	2	APP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
APP	1,744	Binding:1699, Functional:44, ADMET:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
APP	1,744

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 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)
FLORBETAPIR F 18	4	APP
FLORBETAPIR	4	APP
METHYLENE BLUE CATION	4	APP
FLUTEMETAMOL F 18	4	APP
TRETINOIN	4	APP
METHYLENE BLUE ANHYDROUS	4	APP
CLIOQUINOL	4	APP
DONEPEZIL	4	APP
FLORBETABEN F18	4	APP
NIACIN	4	APP
FLUTEMETAMOL	4	APP
GENTIAN VIOLET	4	APP
AMODIAQUINE	4	APP
CARVEDILOL	4	APP
CHLOROQUINE	4	APP
TACRINE	4	APP
RETINOL	4	APP
CURCUMIN	3	APP
CAFFEIC ACID	3	APP
TRAMIPROSATE	3	APP
RESVERATROL	3	APP
FLUTAFURANOL	3	APP
EPIGALOCATECHIN GALLATE	3	APP
LANABECESTAT	3	APP
QUERCETIN	3	APP
EDETIC ACID	3	APP
PARAROSANILINE	2	APP
LUTEOLIN	2	APP
PITTSBURGH COMPOUND B	2	APP
AFTOBETIN	2	APP

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	APP
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	3	DEPDC5, NPRL2, NPRL3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DEPDC5	0	—
NPRL2	0	—
NPRL3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.