autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

Summary

autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (MONDO:0014493) is a disease caused by CTLA4 (GenCC Strong), with 4 cohort genes and 3 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CTLA4 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 271
• Phenotypes (HPO): 31
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0004313	Decreased circulating antibody level	Very frequent (80-99%)
HP:0001047	Atopic dermatitis	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001890	Autoimmune hemolytic anemia	Frequent (30-79%)
HP:0001973	Autoimmune thrombocytopenia	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002090	Pneumonia	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002716	Lymphadenopathy	Frequent (30-79%)
HP:0002720	Decreased circulating IgA level	Frequent (30-79%)
HP:0002783	Recurrent lower respiratory tract infections	Frequent (30-79%)
HP:0002788	Recurrent upper respiratory tract infections	Frequent (30-79%)
HP:0002850	Decreased circulating total IgM	Frequent (30-79%)
HP:0004315	Decreased circulating IgG level	Frequent (30-79%)
HP:0000964	Eczematoid dermatitis	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001904	Neutropenia in presence of anti-neutropil antibodies	Occasional (5-29%)
HP:0002037	Inflammation of the large intestine	Occasional (5-29%)
HP:0002110	Bronchiectasis	Occasional (5-29%)
HP:0002582	Atrophic gastritis	Occasional (5-29%)
HP:0002665	Lymphoma	Occasional (5-29%)
HP:0003765	Psoriasiform dermatitis	Occasional (5-29%)
HP:0005401	Recurrent candida infections	Occasional (5-29%)
HP:0032216	Lymphocytic infiltration of the colorectal mucosa	Occasional (5-29%)
HP:0100280	Crohn’s disease	Occasional (5-29%)
HP:0100646	Thyroiditis	Occasional (5-29%)
HP:0100651	Type I diabetes mellitus	Occasional (5-29%)
HP:0100806	Sepsis	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Very rare (<1-4%)
HP:0012410	Pure red cell aplasia	Very rare (<1-4%)
HP:0100653	Optic neuritis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
Mondo ID	MONDO:0014493
OMIM	616100
Orphanet	436159
NCIT	C126341
UMLS	C4015214
MedGen	863651
GARD	0012316
Is cancer (heuristic)	no

Also known as: ALPS due to CTLA4 haploinsufficiency · ALPS type 5 · ALPS type V · ALPS5 · autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency · autoimmune lymphoproliferative syndrome type 5 · autoimmune lymphoproliferative syndrome type V · autoimmune lymphoproliferative syndrome, type V · CHAI · chai · CTLA-4 haploinsufficiency with autoimmune infiltration disease · CTLA4 haploinsufficiency · immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation

Data availability: 271 ClinVar variants · 37 ClinGen variant curations · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › hypersensitivity reaction disease › type IV hypersensitivity disease › autoimmune lymphoproliferative syndrome › autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

Related subtypes (8): autoimmune lymphoproliferative syndrome type 1, autoimmune lymphoproliferative syndrome type 2A, autoimmune lymphoproliferative syndrome type 2B, autoimmune lymphoproliferative syndrome type 4, Castleman-Kojima disease, FAS-related autoimmune lymphoproliferative immune disorder, type 3 autoimmune lymphoproliferative syndrome, autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD

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

271 retrieved; paginated sample, class counts are floors:

118 uncertain significance, 63 likely benign, 40 pathogenic, 19 benign, 18 likely pathogenic, 10 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
833421	NC_000002.12:g.(?203444868)(203957883_?)del	CD28	Pathogenic	criteria provided, single submitter
1029948	NM_005214.5(CTLA4):c.226C>T (p.Gln76Ter)	CTLA4	Pathogenic	criteria provided, multiple submitters, no conflicts
1071971	NC_000002.11:g.(?204731519)(204732794_?)del	CTLA4	Pathogenic	criteria provided, single submitter
1439020	NM_005214.5(CTLA4):c.71_72del (p.Leu24fs)	CTLA4	Pathogenic	reviewed by expert panel
1449408	NM_005214.5(CTLA4):c.238C>T (p.Gln80Ter)	CTLA4	Pathogenic	criteria provided, single submitter
161109	NM_005214.5(CTLA4):c.151C>T (p.Arg51Ter)	CTLA4	Pathogenic	reviewed by expert panel
161110	NM_005214.5(CTLA4):c.75del (p.Leu28fs)	CTLA4	Pathogenic	reviewed by expert panel
161111	NM_005214.5(CTLA4):c.567+5G>C	CTLA4	Pathogenic	no assertion criteria provided
161112	NM_005214.5(CTLA4):c.105C>A (p.Cys35Ter)	CTLA4	Pathogenic	reviewed by expert panel
161114	NM_005214.5(CTLA4):c.208C>T (p.Arg70Trp)	CTLA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2097298	NM_005214.5(CTLA4):c.216dup (p.Val73fs)	CTLA4	Pathogenic	criteria provided, single submitter
2128011	NM_005214.5(CTLA4):c.160G>C (p.Ala54Pro)	CTLA4	Pathogenic	criteria provided, single submitter
2151958	NM_005214.5(CTLA4):c.450T>G (p.Tyr150Ter)	CTLA4	Pathogenic	criteria provided, single submitter
2151959	NM_005214.5(CTLA4):c.494G>A (p.Trp165Ter)	CTLA4	Pathogenic	criteria provided, single submitter
2425320	NC_000002.11:g.(?204734049)(204737535_?)del	CTLA4	Pathogenic	criteria provided, single submitter
2704586	NM_005214.5(CTLA4):c.415T>C (p.Tyr139His)	CTLA4	Pathogenic	criteria provided, single submitter
280759	NM_005214.5(CTLA4):c.60G>A (p.Trp20Ter)	CTLA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3384671	NM_005214.5(CTLA4):c.346del (p.Ile116fs)	CTLA4	Pathogenic	no assertion criteria provided
3722056	NM_005214.5(CTLA4):c.271dup (p.Met91fs)	CTLA4	Pathogenic	criteria provided, single submitter
4277914	NM_005214.5(CTLA4):c.2T>C (p.Met1Thr)	CTLA4	Pathogenic	criteria provided, single submitter
4683125	NM_005214.5(CTLA4):c.94_101delinsTTCTCTTCATCA (p.Pro32fs)	CTLA4	Pathogenic	reviewed by expert panel
4683126	NM_005214.5(CTLA4):c.361del (p.Ala121fs)	CTLA4	Pathogenic	reviewed by expert panel
4718120	NM_005214.5(CTLA4):c.123_124delinsTT (p.Gln42Ter)	CTLA4	Pathogenic	criteria provided, single submitter
4719495	NM_005214.5(CTLA4):c.174_175del (p.Cys58_Glu59delinsTer)	CTLA4	Pathogenic	criteria provided, single submitter
4732004	NM_005214.5(CTLA4):c.148_165del (p.Ser50_Ser55del)	CTLA4	Pathogenic	criteria provided, single submitter
475277	NM_005214.5(CTLA4):c.420C>A (p.Tyr140Ter)	CTLA4	Pathogenic	criteria provided, single submitter
495051	NM_005214.5(CTLA4):c.412C>A (p.Pro138Thr)	CTLA4	Pathogenic	criteria provided, single submitter
572851	NM_005214.5(CTLA4):c.211del (p.Arg70_Val71insTer)	CTLA4	Pathogenic	criteria provided, single submitter
636389	NM_005214.5(CTLA4):c.457G>A (p.Asp153Asn)	CTLA4	Pathogenic	reviewed by expert panel
644629	NM_005214.5(CTLA4):c.81dup (p.Leu28fs)	CTLA4	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 10 · 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
CTLA4	Strong	Autosomal dominant	autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CTLA4	Orphanet:2584	Classic mycosis fungoides
CTLA4	Orphanet:3162	Sézary syndrome
CTLA4	Orphanet:391490	Adult-onset myasthenia gravis
CTLA4	Orphanet:436159	Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency
CTLA4	Orphanet:536	Systemic lupus erythematosus
CTLA4	Orphanet:900	Granulomatosis with polyangiitis
CD28	Orphanet:2584	Classic mycosis fungoides
CD28	Orphanet:3162	Sézary syndrome
KCNH2	Orphanet:101016	Romano-Ward syndrome
KCNH2	Orphanet:51083	Congenital short QT syndrome

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
CTLA4	HGNC:2505	ENSG00000163599	P16410	Cytotoxic T-lymphocyte protein 4	gencc,clinvar
STRADB	HGNC:13205	ENSG00000082146	Q9C0K7	STE20-related kinase adapter protein beta	clinvar
CD28	HGNC:1653	ENSG00000178562	P10747	T-cell-specific surface glycoprotein CD28	clinvar
KCNH2	HGNC:6251	ENSG00000055118	Q12809	Voltage-gated inwardly rectifying potassium channel KCNH2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CTLA4	Cytotoxic T-lymphocyte protein 4	Inhibitory receptor acting as a major negative regulator of T-cell responses.
STRADB	STE20-related kinase adapter protein beta	Pseudokinase which, in complex with CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta), binds to and activates STK11/LKB1.
CD28	T-cell-specific surface glycoprotein CD28	Receptor that plays a role in T-cell activation, proliferation, survival and the maintenance of immune homeostasis.
KCNH2	Voltage-gated inwardly rectifying potassium channel KCNH2	Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel.

Protein-family classification

Druggable: 4 · 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
Antibody/Immunoglobulin	2	14.6×	0.020
Ion channel	1	27.9×	0.053
Kinase	1	6.9×	0.137

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CTLA4	Antibody/Immunoglobulin	yes		Ig_sub, CTLA4, Ig_V-set
STRADB	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, STRAD_A/B-like
CD28	Antibody/Immunoglobulin	yes		CD28, Ig_V-set, Ig-like_fold
KCNH2	Ion channel	yes		PAS, cNMP-bd_dom, PAS-assoc_C

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
lymph node	2
vermiform appendix	2
buccal mucosa cell	1
adrenal tissue	1
right adrenal gland	1
right adrenal gland cortex	1
blood	1
apex of heart	1
cardiac atrium	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CTLA4	164	tissue_specific	marker	lymph node, vermiform appendix, buccal mucosa cell
STRADB	140	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
CD28	154	broad	marker	lymph node, vermiform appendix, blood
KCNH2	211	broad	marker	apex of heart, right atrium auricular region, cardiac atrium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CTLA4	3,863
CD28	2,958
KCNH2	1,932
STRADB	882

Intra-cohort edges

A	B	Sources
CD28	CTLA4	intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNH2	Q12809	24
CTLA4	P16410	22
CD28	P10747	10

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
STRADB	Q9C0K7	74.39

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. 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
Co-stimulation by CD28	2	190.3×	0.001	CTLA4, CD28
Nef mediated downregulation of CD28 cell surface expression	1	1427.5×	0.011	CD28
Phase 3 - rapid repolarisation	1	285.5×	0.028	KCNH2
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	1	285.5×	0.028	CTLA4
CD28 dependent Vav1 pathway	1	219.6×	0.029	CD28
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1	158.6×	0.029	CD28
The role of Nef in HIV-1 replication and disease pathogenesis	1	158.6×	0.029	CD28
Co-inhibition by CTLA4	1	129.8×	0.029	CTLA4
Regulation of T cell activation by CD28 family	1	105.7×	0.029	CD28
Energy dependent regulation of mTOR by LKB1-AMPK	1	98.5×	0.029	STRADB
CD28 dependent PI3K/Akt signaling	1	98.5×	0.029	CD28
PI3K/AKT Signaling in Cancer	1	92.1×	0.029	CD28
Host Interactions of HIV factors	1	84.0×	0.029	CD28
Negative regulation of the PI3K/AKT network	1	69.6×	0.032	CD28
MTOR signalling	1	66.4×	0.032	STRADB
Voltage gated Potassium channels	1	60.7×	0.033	KCNH2
Potassium Channels	1	33.6×	0.055	KCNH2
Constitutive Signaling by Aberrant PI3K in Cancer	1	31.7×	0.055	CD28
HIV Infection	1	29.7×	0.056	CD28
Cardiac conduction	1	27.2×	0.058	KCNH2
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	24.2×	0.062	CD28
Intracellular signaling by second messengers	1	22.8×	0.063	CD28
Muscle contraction	1	19.3×	0.068	KCNH2
Signal Transduction	2	5.1×	0.068	STRADB, CD28
PIP3 activates AKT signaling	1	16.7×	0.075	CD28
Diseases of signal transduction by growth factor receptors and second messengers	1	14.2×	0.084	CD28
Neuronal System	1	11.1×	0.104	KCNH2
Viral Infection Pathways	1	7.7×	0.141	CD28
Adaptive Immune System	1	7.5×	0.141	CD28
Infectious disease	1	6.2×	0.162	CD28

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
regulation of heart rate by hormone	1	2106.5×	0.011	KCNH2
positive regulation of inflammatory response to antigenic stimulus	1	1404.3×	0.011	CD28
negative regulation of regulatory T cell differentiation	1	842.6×	0.011	CTLA4
negative regulation of potassium ion export across plasma membrane	1	601.9×	0.011	KCNH2
regulatory T cell differentiation	1	526.6×	0.011	CD28
CD4-positive, alpha-beta T cell proliferation	1	468.1×	0.011	CD28
regulation of regulatory T cell differentiation	1	468.1×	0.011	CD28
membrane depolarization during action potential	1	421.3×	0.011	KCNH2
membrane repolarization during action potential	1	421.3×	0.011	KCNH2
membrane repolarization during cardiac muscle cell action potential	1	421.3×	0.011	KCNH2
membrane repolarization during ventricular cardiac muscle cell action potential	1	421.3×	0.011	KCNH2
positive regulation of CD4-positive, alpha-beta T cell proliferation	1	421.3×	0.011	CD28
activation of protein kinase activity	1	383.0×	0.011	STRADB
positive regulation of isotype switching to IgG isotypes	1	383.0×	0.011	CD28
negative thymic T cell selection	1	351.1×	0.011	CD28
negative regulation of potassium ion transmembrane transport	1	351.1×	0.011	KCNH2
regulation of membrane repolarization	1	324.1×	0.011	KCNH2
membrane repolarization	1	324.1×	0.011	KCNH2
T cell receptor signaling pathway	2	75.9×	0.011	CTLA4, CD28
potassium ion export across plasma membrane	1	263.3×	0.012	KCNH2
ventricular cardiac muscle cell action potential	1	247.8×	0.012	KCNH2
positive regulation of potassium ion transmembrane transport	1	247.8×	0.012	KCNH2
negative regulation of B cell proliferation	1	234.1×	0.012	CTLA4
regulation of ventricular cardiac muscle cell membrane repolarization	1	210.7×	0.013	KCNH2
positive regulation of T cell receptor signaling pathway	1	191.5×	0.013	CD28
potassium ion homeostasis	1	191.5×	0.013	KCNH2
regulation of potassium ion transmembrane transport	1	156.0×	0.016	KCNH2
positive regulation of viral genome replication	1	145.3×	0.016	CD28
positive regulation of interleukin-4 production	1	140.4×	0.016	CD28
positive regulation of mitotic nuclear division	1	135.9×	0.016	CD28

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 4 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
KCNH2	CETIRIZINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNH2	706	4
CTLA4	0	0
STRADB	0	0
CD28	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CETIRIZINE	4	KCNH2
BEPRIDIL	4	KCNH2
BEXAROTENE	4	KCNH2
CLOTRIMAZOLE	4	KCNH2
MORICIZINE	4	KCNH2
PROPIVERINE	4	KCNH2
SUVOREXANT	4	KCNH2
ACETOPHENAZINE	4	KCNH2
DIBUCAINE	4	KCNH2
MESORIDAZINE	4	KCNH2
NIRAPARIB	4	KCNH2
BUPIVACAINE	4	KCNH2
IMIPRAMINE	4	KCNH2
BIPERIDEN	4	KCNH2
EPINASTINE	4	KCNH2
HALOFANTRINE	4	KCNH2
DROPERIDOL	4	KCNH2
RIMONABANT	4	KCNH2
ALOSETRON	4	KCNH2
ARIPIPRAZOLE	4	KCNH2
AMOXAPINE	4	KCNH2
IDARUBICIN	4	KCNH2
DICYCLOMINE	4	KCNH2
TELITHROMYCIN	4	KCNH2
EZETIMIBE	4	KCNH2
SAQUINAVIR	4	KCNH2
VINCAMINE	4	KCNH2
PONATINIB	4	KCNH2
DESLORATADINE	4	KCNH2
PRUCALOPRIDE	4	KCNH2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNH2	4,851	Binding:3558, Toxicity:1071, Functional:169, ADMET:53
STRADB	20	Binding:20
CTLA4	1	Binding:1
CD28	1	Functional:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
KCNH2	4,851

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)
CETIRIZINE	4	KCNH2
BEPRIDIL	4	KCNH2
BEXAROTENE	4	KCNH2
CLOTRIMAZOLE	4	KCNH2
MORICIZINE	4	KCNH2
PROPIVERINE	4	KCNH2
SUVOREXANT	4	KCNH2
ACETOPHENAZINE	4	KCNH2
DIBUCAINE	4	KCNH2
MESORIDAZINE	4	KCNH2
NIRAPARIB	4	KCNH2
BUPIVACAINE	4	KCNH2
IMIPRAMINE	4	KCNH2
BIPERIDEN	4	KCNH2
EPINASTINE	4	KCNH2
HALOFANTRINE	4	KCNH2
DROPERIDOL	4	KCNH2
RIMONABANT	4	KCNH2
ALOSETRON	4	KCNH2
ARIPIPRAZOLE	4	KCNH2
AMOXAPINE	4	KCNH2
IDARUBICIN	4	KCNH2
DICYCLOMINE	4	KCNH2
TELITHROMYCIN	4	KCNH2
EZETIMIBE	4	KCNH2
SAQUINAVIR	4	KCNH2
VINCAMINE	4	KCNH2
PONATINIB	4	KCNH2
DESLORATADINE	4	KCNH2
PRUCALOPRIDE	4	KCNH2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNH2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	CTLA4, CD28
D	Druggable family + AlphaFold only, no drug	1	STRADB
E	Difficult family or no structure, no drug	0

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)
CTLA4	1	—
STRADB	20	—
CD28	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05235438	PHASE1	UNKNOWN	Safety and Toxicity Study of IMM27M in Patients With Advanced Solid Tumor
NCT04377867	Not specified	UNKNOWN	New Biomarkers for Diagnosis and Follow-up of Patients With LRBA or CTLA4 Deficiencies
NCT05040256	Not specified	COMPLETED	Neurologic and Immunologic Characteristics of CTLA-4 and LRBA Hereditary Deficiency