Autoimmune lymphoproliferative syndrome

Summary

Autoimmune lymphoproliferative syndrome (MONDO:0017979) is a disease (an umbrella term covering 9 Mondo subtypes) caused by variants in FAS and FASLG, with 7 cohort genes and 6 clinical trials. The dominant Reactome pathway is FasL/ CD95L signaling (3 cohort genes). Top therapeutic interventions include sirolimus, valproic acid, and soquelitinib.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal genes: FAS (GenCC Definitive), FASLG (GenCC Strong)
• Umbrella term: 9 Mondo subtypes
• Cohort genes: 7
• ClinVar variants: 2
• Phenotypes (HPO): 72
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		500	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

72 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001744	Splenomegaly	Very frequent (80-99%)
HP:0002716	Lymphadenopathy	Very frequent (80-99%)
HP:0002730	Chronic noninfectious lymphadenopathy	Very frequent (80-99%)
HP:0002960	Autoimmunity	Very frequent (80-99%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0001890	Autoimmune hemolytic anemia	Frequent (30-79%)
HP:0001892	Abnormal bleeding	Frequent (30-79%)
HP:0001904	Neutropenia in presence of anti-neutropil antibodies	Frequent (30-79%)
HP:0001971	Hypersplenism	Frequent (30-79%)
HP:0001973	Autoimmune thrombocytopenia	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002851	Elevated proportion of CD4-negative, CD8-negative, alpha-beta regulatory T cells	Frequent (30-79%)
HP:0003237	Increased circulating IgG level	Frequent (30-79%)
HP:0005404	Increased B cell count	Frequent (30-79%)
HP:0010702	Increased circulating antibody level	Frequent (30-79%)
HP:0030886	Abnormal lymphocyte apoptosis	Frequent (30-79%)
HP:0033199	Increased circulating interleukin 10 concentration	Frequent (30-79%)
HP:0011117	Abnormal circulating interleukin concentration	Frequent (30-79%)
HP:0000099	Glomerulonephritis	Occasional (5-29%)
HP:0001025	Urticaria	Occasional (5-29%)
HP:0001880	Eosinophilia	Occasional (5-29%)
HP:0001888	Lymphopenia	Occasional (5-29%)
HP:0001923	Reticulocytosis	Occasional (5-29%)
HP:0002633	Vasculitis	Occasional (5-29%)
HP:0002848	Specific anti-polysaccharide antibody deficiency	Occasional (5-29%)
HP:0002850	Decreased circulating total IgM	Occasional (5-29%)
HP:0002923	Rheumatoid factor positive	Occasional (5-29%)
HP:0003212	Increased circulating IgE level	Occasional (5-29%)
HP:0003261	Increased circulating IgA level	Occasional (5-29%)
HP:0003453	Antineutrophil antibody positivity	Occasional (5-29%)
HP:0003493	Antinuclear antibody positivity	Occasional (5-29%)
HP:0003613	Antiphospholipid antibody positivity	Occasional (5-29%)
HP:0004315	Decreased circulating IgG level	Occasional (5-29%)
HP:0004844	Coombs-positive hemolytic anemia	Occasional (5-29%)
HP:0012115	Hepatitis	Occasional (5-29%)
HP:0012189	Hodgkin lymphoma	Occasional (5-29%)
HP:0012190	T-cell lymphoma	Occasional (5-29%)
HP:0012191	B-cell lymphoma	Occasional (5-29%)
HP:0012539	Non-Hodgkin lymphoma	Occasional (5-29%)
HP:0030080	Burkitt lymphoma	Occasional (5-29%)
HP:0031392	Abnormal proportion of CD4 T cells	Occasional (5-29%)
HP:0031393	Abnormal proportion of CD8 T cells	Occasional (5-29%)
HP:0034447	Increased circulating interleukin 18 concentration	Occasional (5-29%)
HP:0040126	Abnormal vitamin B12 level	Occasional (5-29%)
HP:0100646	Thyroiditis	Occasional (5-29%)
HP:0100827	Lymphocytosis	Occasional (5-29%)
HP:6000016	Elevated circulating vitamin B12 concentration	Occasional (5-29%)
HP:6000017	Elevated circulating soluble FASL concentration	Occasional (5-29%)
HP:0032218	Decreased proportion of CD4-positive T cells	Occasional (5-29%)
HP:0000083	Renal insufficiency	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autoimmune lymphoproliferative syndrome
Mondo ID	MONDO:0017979
MeSH	D056735
Orphanet	3261
DOID	DOID:6688
ICD-10-CM	D89.82
ICD-11	1072688797
NCIT	C37864
GARD	0008686
MedDRA	10069521
Is cancer (heuristic)	no

Also known as: ALPS · ALPS (autoimmune lymphoproliferative syndrome) · autoimmune lymphoproliferative syndrome type 1, autosomal dominant · Canale-Smith syndrome · FAS deficiency

Data availability: 2 ClinVar variants · 9 GenCC gene-disease records.

Disease family

An umbrella term covering 9 Mondo subtypes.

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

Related subtypes (2): cryoglobulinemia, serum sickness

Subtypes (9): autoimmune lymphoproliferative syndrome type 1, autoimmune lymphoproliferative syndrome type 2A, autoimmune lymphoproliferative syndrome type 2B, autoimmune lymphoproliferative syndrome type 4, autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency, 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

2 retrieved; paginated sample, class counts are floors:

2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3572951	NC_000010.10:g.90533969_90911342del	ACTA2	Pathogenic	criteria provided, single submitter
3376841	NM_000043.6(FAS):c.381C>A (p.Cys127Ter)	FAS	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 32 · 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
FAS	Definitive	Autosomal dominant	autoimmune lymphoproliferative syndrome type 1	7
FASN	Definitive	Autosomal dominant	autoimmune lymphoproliferative syndrome type 1	8
CASP10	Strong	Autosomal dominant	autoimmune lymphoproliferative syndrome type 2A	3
FASLG	Strong	Autosomal recessive	autoimmune lymphoproliferative syndrome type 1	6
PRKCD	Strong	Autosomal recessive	autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD	5
RASGRP1	Supportive	Autosomal dominant	autoimmune lymphoproliferative syndrome	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FAS	Orphanet:117	Behçet disease
FAS	Orphanet:3261	Autoimmune lymphoproliferative syndrome
FAS	Orphanet:3437	Vogt-Koyanagi-Harada disease
FASLG	Orphanet:3261	Autoimmune lymphoproliferative syndrome
CASP10	Orphanet:3261	Autoimmune lymphoproliferative syndrome
PRKCD	Orphanet:664711	EBV-induced lymphoproliferative disease due to PRKCD deficiency
RASGRP1	Orphanet:664699	EBV-induced lymphoproliferative disease due to RASGRP1 deficiency
ACTA2	Orphanet:2573	Moyamoya disease
ACTA2	Orphanet:404463	Multisystemic smooth muscle dysfunction syndrome
ACTA2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FAS	HGNC:11920	ENSG00000026103	P25445	Tumor necrosis factor receptor superfamily member 6	gencc,clinvar
FASN	HGNC:3594	ENSG00000169710	P49327	Fatty acid synthase	gencc,clinvar
FASLG	HGNC:11936	ENSG00000117560	P48023	Tumor necrosis factor ligand superfamily member 6	gencc
CASP10	HGNC:1500	ENSG00000003400	Q92851	Caspase-10	gencc
PRKCD	HGNC:9399	ENSG00000163932	Q05655	Protein kinase C delta type	gencc
RASGRP1	HGNC:9878	ENSG00000172575	O95267	RAS guanyl-releasing protein 1	gencc
ACTA2	HGNC:130	ENSG00000107796	P62736	Actin, aortic smooth muscle	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FAS	Tumor necrosis factor receptor superfamily member 6	Receptor for TNFSF6/FASLG.
FASN	Fatty acid synthase	Fatty acid synthetase is a multifunctional enzyme that catalyzes the de novo biosynthesis of long-chain saturated fatty acids starting from acetyl-CoA and malonyl-CoA in the presence of NADPH.
FASLG	Tumor necrosis factor ligand superfamily member 6	Cytokine that binds to TNFRSF6/FAS, a receptor that transduces the apoptotic signal into cells.
CASP10	Caspase-10	Involved in the activation cascade of caspases responsible for apoptosis execution.
PRKCD	Protein kinase C delta type	Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays contrasting roles in cell death and cell survival by functioning as a pro-apoptotic protein during DNA damage-induced apoptosi…
RASGRP1	RAS guanyl-releasing protein 1	Functions as a calcium- and diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP.
ACTA2	Actin, aortic smooth muscle	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.43

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
Enzyme (other)	2	3.4×	0.330
Kinase	1	4.0×	0.340
Other/Unknown	4	1.0×	0.626

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FAS	Other/Unknown	no		Death_dom, TNFR/NGFR_Cys_rich_reg, Fas_rcpt
FASN	Enzyme (other)	yes	2.3.1.39	Thioesterase, Ac_transferase_dom_sf, Ppantetheine_attach_site
FASLG	Other/Unknown	no		TNF_dom, TNF, Tumour_necrosis_fac-like_dom
CASP10	Enzyme (other)	yes	3.4.22.63	Pept_C14_p20, DED_dom, Pept_C14_p10
PRKCD	Kinase	yes	2.7.11.13	C2_dom, Prot_kinase_dom, AGC-kinase_C
RASGRP1	Other/Unknown	no		Ras-like_Gua-exchang_fac_N, RASGEF_cat_dom, EF_hand_dom
ACTA2	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
monocyte	2
left ovary	1
rectum	1
right ovary	1
endometrium epithelium	1
right hemisphere of cerebellum	1
skin of abdomen	1
blood	1
lymph node	1
colonic epithelium	1
leukocyte	1
mononuclear cell	1
Brodmann (1909) area 23	1
cerebellar vermis	1
pons	1
blood vessel layer	1
cauda epididymis	1
saphenous vein	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FAS	280	ubiquitous	marker	rectum, left ovary, right ovary
FASN	273	ubiquitous	marker	right hemisphere of cerebellum, endometrium epithelium, skin of abdomen
FASLG	118	tissue_specific	marker	granulocyte, blood, lymph node
CASP10	206	ubiquitous	marker	colonic epithelium, granulocyte, monocyte
PRKCD	229	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
RASGRP1	248	broad	marker	pons, cerebellar vermis, Brodmann (1909) area 23
ACTA2	289	ubiquitous	marker	cauda epididymis, blood vessel layer, saphenous vein

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FASN	6,551
FASLG	4,373
FAS	3,314
PRKCD	3,286
RASGRP1	1,939
CASP10	1,242
ACTA2	774

Intra-cohort edges

A	B	Sources
CASP10	FAS	intact, string_interaction
CASP10	FASLG	biogrid_interaction, string_interaction
FAS	FASLG	intact, string_interaction

Structural data

PDB: 5 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FASN	P49327	34
FAS	P25445	7
FASLG	P48023	3
PRKCD	Q05655	2
RASGRP1	O95267	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACTA2	P62736	95.43
CASP10	Q92851	69.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 93. Enrichment computed across 7 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
FasL/ CD95L signaling	3	978.9×	1e-07	FAS, FASLG, CASP10
Regulation by c-FLIP	2	296.6×	4e-04	FAS, FASLG
CASP8 activity is inhibited	2	296.6×	4e-04	FAS, FASLG
Dimerization of procaspase-8	2	296.6×	4e-04	FAS, FASLG
Caspase activation via Death Receptors in the presence of ligand	2	217.5×	6e-04	FAS, FASLG
Effects of PIP2 hydrolysis	2	130.5×	0.001	PRKCD, RASGRP1
RIPK1-mediated regulated necrosis	2	130.5×	0.001	FAS, FASLG
Activation of RAS in B cells	1	326.3×	0.036	RASGRP1
TRAIL signaling	1	203.9×	0.043	CASP10
ChREBP activates metabolic gene expression	1	181.3×	0.043	FASN
HuR (ELAVL1) binds and stabilizes mRNA	1	181.3×	0.043	PRKCD
NR1H2 & NR1H3 regulate gene expression linked to lipogenesis	1	163.1×	0.043	FASN
TP53 Regulates Transcription of Caspase Activators and Caspases	1	135.9×	0.043	CASP10
TP53 Regulates Transcription of Death Receptors and Ligands	1	135.9×	0.043	FAS
Regulation of CDH1 Function	1	135.9×	0.043	ACTA2
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	1	125.5×	0.043	CASP10
Vitamin B5 (pantothenate) metabolism	1	108.8×	0.043	FASN
Regulation of mRNA stability by proteins that bind AU-rich elements	1	108.8×	0.043	PRKCD
Rap1 signalling	1	102.0×	0.043	RASGRP1
FOXO-mediated transcription of cell death genes	1	102.0×	0.043	FASLG
VEGFR2 mediated cell proliferation	1	81.6×	0.043	PRKCD
NOTCH4 Intracellular Domain Regulates Transcription	1	81.6×	0.043	ACTA2
TP53 Regulates Transcription of Cell Death Genes	1	77.7×	0.043	CASP10
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	77.7×	0.043	ACTA2
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	74.2×	0.043	FASLG
Signaling by NOTCH4	1	70.9×	0.043	ACTA2
Apoptotic cleavage of cellular proteins	1	68.0×	0.043	PRKCD
SHC1 events in ERBB2 signaling	1	68.0×	0.043	PRKCD
Apoptotic execution phase	1	68.0×	0.043	PRKCD
Role of phospholipids in phagocytosis	1	65.3×	0.043	PRKCD

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
necroptotic signaling pathway	2	601.9×	5e-04	FAS, FASLG
positive regulation of apoptotic signaling pathway	2	166.0×	0.003	FAS, PRKCD
apoptotic process	4	16.4×	0.003	FAS, FASLG, CASP10, PRKCD
B cell proliferation	2	137.6×	0.003	PRKCD, RASGRP1
extrinsic apoptotic signaling pathway via death domain receptors	2	114.6×	0.003	FAS, FASLG
extrinsic apoptotic signaling pathway	2	87.5×	0.005	FAS, FASLG
positive regulation of hepatic stellate cell contraction	1	2407.4×	0.005	ACTA2
positive regulation of phospholipid scramblase activity	1	2407.4×	0.005	PRKCD
positive regulation of phosphatidylserine exposure on apoptotic cell surface	1	2407.4×	0.005	FASLG
positive regulation of glucosylceramide catabolic process	1	2407.4×	0.005	PRKCD
positive regulation of neuron apoptotic process	2	77.7×	0.005	FASLG, CASP10
signal transduction	4	9.2×	0.005	FAS, FASLG, PRKCD, RASGRP1
inflammatory cell apoptotic process	1	1203.7×	0.007	FASLG
positive regulation of hepatic stellate cell migration	1	1203.7×	0.007	ACTA2
release of sequestered calcium ion into cytosol by endoplasmic reticulum	1	1203.7×	0.007	FASLG
positive regulation of sphingomyelin catabolic process	1	1203.7×	0.007	PRKCD
termination of signal transduction	1	802.5×	0.007	PRKCD
secretory granule localization	1	802.5×	0.007	RASGRP1
Fas signaling pathway	1	802.5×	0.007	FAS
retinal cell programmed cell death	1	802.5×	0.007	FASLG
juxtaglomerular apparatus development	1	802.5×	0.007	ACTA2
regulation of ceramide biosynthetic process	1	802.5×	0.007	PRKCD
protein kinase C signaling	1	601.9×	0.009	PRKCD
glomerular mesangial cell development	1	601.9×	0.009	ACTA2
vascular associated smooth muscle contraction	1	481.5×	0.009	ACTA2
negative regulation of filopodium assembly	1	481.5×	0.009	PRKCD
cellular response to hyperoxia	1	481.5×	0.009	FAS
mesenchyme migration	1	481.5×	0.009	ACTA2
phospholipase C/protein kinase C signal transduction	1	401.2×	0.011	PRKCD
positive regulation of hepatic stellate cell activation	1	401.2×	0.011	ACTA2

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 5

Druggability breadth: 6 of 7 evidence-associated genes (86%) 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
FASN	RABEPRAZOLE
PRKCD	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKCD	49	4
FASN	8	4
FAS	0	0
FASLG	0	0
CASP10	0	0
RASGRP1	0	0
ACTA2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
RABEPRAZOLE	4	FASN
PANTOPRAZOLE	4	FASN
OMEPRAZOLE	4	FASN
ORLISTAT	4	FASN
LANSOPRAZOLE	4	FASN
INGENOL MEBUTATE	4	PRKCD
MIDOSTAURIN	4	PRKCD
TAMOXIFEN	4	PRKCD
TOFACITINIB CITRATE	4	PRKCD
BARICITINIB	4	PRKCD
TOFACITINIB	4	PRKCD
CAPIVASERTIB	4	PRKCD
BOSUTINIB	4	PRKCD
ABEMACICLIB	4	PRKCD
EPIGALOCATECHIN GALLATE	3	FASN
SURAMIN	3	PRKCD
FASUDIL	3	PRKCD
ALVOCIDIB	3	PRKCD
CURCUMIN	3	PRKCD
CRENOLANIB	3	PRKCD
ENZASTAURIN	3	PRKCD
RIPASUDIL	3	PRKCD
DOVITINIB	3	PRKCD
LESTAURTINIB	3	PRKCD
RUBOXISTAURIN	3	PRKCD
LUTEOLIN	2	FASN
DENIFANSTAT	2	FASN
PHORBOL MYRISTATE ACETATE	2	PRKCD
EDELFOSINE	2	PRKCD
UPROSERTIB	2	PRKCD

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
PRKCD	804	Binding:790, Functional:14
FASN	142	Binding:136, Functional:6
CASP10	22	Binding:21, Functional:1
FAS	8	Binding:8
RASGRP1	8	Binding:8
FASLG	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FASN	2.3.1.39, 2.3.1.85	[acyl-carrier-protein] S-malonyltransferase, fatty-acid synthase system
CASP10	3.4.22.63	caspase-10
PRKCD	2.7.11.13	protein kinase C

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
FASN	142
PRKCD	804

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; 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)
RABEPRAZOLE	4	FASN
PANTOPRAZOLE	4	FASN
OMEPRAZOLE	4	FASN
ORLISTAT	4	FASN
LANSOPRAZOLE	4	FASN
INGENOL MEBUTATE	4	PRKCD
MIDOSTAURIN	4	PRKCD
TAMOXIFEN	4	PRKCD
TOFACITINIB CITRATE	4	PRKCD
BARICITINIB	4	PRKCD
TOFACITINIB	4	PRKCD
CAPIVASERTIB	4	PRKCD
BOSUTINIB	4	PRKCD
ABEMACICLIB	4	PRKCD
EPIGALOCATECHIN GALLATE	3	FASN
SURAMIN	3	PRKCD
FASUDIL	3	PRKCD
ALVOCIDIB	3	PRKCD
CURCUMIN	3	PRKCD
CRENOLANIB	3	PRKCD
ENZASTAURIN	3	PRKCD
RIPASUDIL	3	PRKCD
DOVITINIB	3	PRKCD
LESTAURTINIB	3	PRKCD
RUBOXISTAURIN	3	PRKCD
LUTEOLIN	2	FASN
DENIFANSTAT	2	FASN
PHORBOL MYRISTATE ACETATE	2	PRKCD
EDELFOSINE	2	PRKCD
UPROSERTIB	2	PRKCD

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	FASN, PRKCD
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	CASP10
E	Difficult family or no structure, no drug	4	FAS, FASLG, RASGRP1, ACTA2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FAS	8	—
FASLG	2	—
CASP10	22	—
RASGRP1	8	—
ACTA2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	2
PHASE2	2
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT06730126	PHASE2	RECRUITING	Study of the ITK Inhibitor Soquelitinib to Reduce Lymphoproliferation and Improve Cytopenias in Autoimmune Lymphoproliferative Syndrome (ALPS)-FAS Patients
NCT00392951	PHASE1/PHASE2	COMPLETED	Sirolimus for Autoimmune Disease of Blood Cells
NCT00605657	PHASE1/PHASE2	COMPLETED	Valproic Acid (Depakote[Registered Trademark]) to Treat Autoimmune Lymphoproliferative Syndrome (ALPS)
NCT04902807	Not specified	RECRUITING	Conception of a Diagnosis, Prognosis and Therapeutic Decision Tool for Patients With Autoimmunity and Inflammation
NCT01672918	Not specified	WITHDRAWN	Fluorodeoxyglucose Imaging Studies to Detect Lymphoma

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SIROLIMUS	4	1
VALPROIC ACID	4	1
SOQUELITINIB	2	1