Autoimmune lymphoproliferative syndrome type 1

Summary

Autoimmune lymphoproliferative syndrome type 1 (MONDO:0011158) is a disease caused by variants in FAS and FASLG, with 9 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

• Causal genes: FAS (GenCC Definitive), FASLG (GenCC Strong)
• Cohort genes: 9
• ClinVar variants: 646
• Clinical trials: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autoimmune lymphoproliferative syndrome type 1
Mondo ID	MONDO:0011158
OMIM	601859
SNOMED CT	702444009
UMLS	C1328840
MedGen	231300
GARD	0024776
Is cancer (heuristic)	no

Also known as: ALPS · autoimmune lymphoproliferative syndrome · autoimmune lymphoproliferative syndrome type 1 · autoimmune lymphoproliferative syndrome, type 1A · autoimmune lymphoproliferative syndrome, type 1B · autoimmune lymphoproliferative syndrome, type IA · autoimmune lymphoproliferative syndrome, type IB

Data availability: 646 ClinVar variants · 7 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 type 1

Related subtypes (8): 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

600 retrieved; paginated sample, class counts are floors:

269 uncertain significance, 178 likely benign, 59 pathogenic, 29 benign, 23 likely pathogenic, 20 conflicting classifications of pathogenicity, 12 benign/likely benign, 7 pathogenic/likely pathogenic, 3 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1459384	NC_000010.10:g.(?90749963)(90750683_?)del	ACTA2	Pathogenic	criteria provided, single submitter
831277	NC_000010.11:g.(?88989499)(89247668_?)del	ACTA2	Pathogenic	criteria provided, single submitter
1067934	NM_000043.6(FAS):c.778G>A (p.Asp260Asn)	FAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1070181	NM_000043.6(FAS):c.676+1G>T	FAS	Pathogenic	criteria provided, single submitter
1070182	NM_000043.6(FAS):c.749G>A (p.Arg250Gln)	FAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070958	NM_000043.6(FAS):c.442A>T (p.Lys148Ter)	FAS	Pathogenic	criteria provided, single submitter
1071139	NM_000043.6(FAS):c.644T>A (p.Leu215Ter)	FAS	Pathogenic	criteria provided, single submitter
1074734	NM_000043.6(FAS):c.657del (p.Val220fs)	FAS	Pathogenic	criteria provided, single submitter
1357498	NM_000043.6(FAS):c.816del (p.Glu272fs)	FAS	Pathogenic	criteria provided, single submitter
1373595	NM_000043.6(FAS):c.707_708insG (p.Ile236fs)	FAS	Pathogenic	criteria provided, single submitter
1395111	NM_000043.6(FAS):c.332A>G (p.His111Arg)	FAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1413808	NM_000043.6(FAS):c.182_183insTTAT (p.Lys61fs)	FAS	Pathogenic	criteria provided, single submitter
1443489	NM_000043.6(FAS):c.312dup (p.Arg105Ter)	FAS	Pathogenic	criteria provided, single submitter
1451181	NM_000043.6(FAS):c.259G>T (p.Glu87Ter)	FAS	Pathogenic	criteria provided, single submitter
1455090	NM_000043.6(FAS):c.403del (p.Cys135fs)	FAS	Pathogenic	criteria provided, single submitter
1457614	NM_000043.6(FAS):c.528G>A (p.Trp176Ter)	FAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1506283	NM_000043.6(FAS):c.506-16A>G	FAS	Pathogenic	criteria provided, single submitter
16498	NM_000043.6(FAS):c.334+2dup	FAS	Pathogenic	criteria provided, single submitter
16501	NM_000043.6(FAS):c.817C>T (p.Gln273Ter)	FAS	Pathogenic	criteria provided, single submitter
16504	NM_000043.6(FAS):c.779A>T (p.Asp260Val)	FAS	Pathogenic	criteria provided, single submitter
16505	NM_000043.6(FAS):c.749G>C (p.Arg250Pro)	FAS	Pathogenic	criteria provided, single submitter
16514	NM_000043.6(FAS):c.651+2T>C	FAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1701144	NM_000043.6(FAS):c.685_686del (p.Leu229fs)	FAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1802177	NM_000043.6(FAS):c.334+2T>C	FAS	Pathogenic	criteria provided, single submitter
2000972	NM_000043.6(FAS):c.356del (p.Cys119fs)	FAS	Pathogenic	criteria provided, single submitter
2005553	NM_000043.6(FAS):c.498del (p.Glu167fs)	FAS	Pathogenic	criteria provided, single submitter
2083676	NM_000043.6(FAS):c.857G>A (p.Gly286Glu)	FAS	Pathogenic	criteria provided, single submitter
2130948	NM_000043.6(FAS):c.676+1G>C	FAS	Pathogenic	criteria provided, single submitter
2136912	NM_000043.6(FAS):c.335-2A>G	FAS	Pathogenic	criteria provided, single submitter
2136914	NM_000043.6(FAS):c.506-1G>C	FAS	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 11 · 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
FASLG	Strong	Autosomal recessive	autoimmune lymphoproliferative syndrome type 1	6

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
ACTA2	Orphanet:2573	Moyamoya disease
ACTA2	Orphanet:404463	Multisystemic smooth muscle dysfunction syndrome
ACTA2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
CASP10	Orphanet:3261	Autoimmune lymphoproliferative syndrome
ITK	Orphanet:538963	Combined immunodeficiency due to ITK deficiency
MYOC	Orphanet:98976	Congenital glaucoma
MYOC	Orphanet:98977	Juvenile glaucoma

Cohort genes → proteins

9 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FAS	HGNC:11920	ENSG00000026103	P25445	Tumor necrosis factor receptor superfamily member 6	gencc,clinvar
FASLG	HGNC:11936	ENSG00000117560	P48023	Tumor necrosis factor ligand superfamily member 6	gencc,clinvar
FASN	HGNC:3594	ENSG00000169710	P49327	Fatty acid synthase	gencc,clinvar
ACTA2	HGNC:130	ENSG00000107796	P62736	Actin, aortic smooth muscle	clinvar
CASP10	HGNC:1500	ENSG00000003400	Q92851	Caspase-10	clinvar
SLC9C2	HGNC:28664	ENSG00000162753	Q5TAH2	Sodium/hydrogen exchanger 11	clinvar
FAS-AS1	HGNC:37128			FAS antisense RNA 1	clinvar
ITK	HGNC:6171	ENSG00000113263	Q08881	Tyrosine-protein kinase ITK/TSK	clinvar
MYOC	HGNC:7610	ENSG00000034971	Q99972	Myocilin	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.
FASLG	Tumor necrosis factor ligand superfamily member 6	Cytokine that binds to TNFRSF6/FAS, a receptor that transduces the apoptotic signal into cells.
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.
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.
CASP10	Caspase-10	Involved in the activation cascade of caspases responsible for apoptosis execution.
SLC9C2	Sodium/hydrogen exchanger 11	Involved in pH regulation.
ITK	Tyrosine-protein kinase ITK/TSK	Tyrosine kinase that plays an essential role in regulation of the adaptive immune response.
MYOC	Myocilin	Secreted glycoprotein regulating the activation of different signaling pathways in adjacent cells to control different processes including cell adhesion, cell-matrix adhesion, cytoskeleton organization and cell migration.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 6 · Druggable fraction: 0.33

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
Kinase	1	3.1×	0.380
Enzyme (other)	2	2.7×	0.380
Other/Unknown	6	1.2×	0.380

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FAS	Other/Unknown	no		Death_dom, TNFR/NGFR_Cys_rich_reg, Fas_rcpt
FASLG	Other/Unknown	no		TNF_dom, TNF, Tumour_necrosis_fac-like_dom
FASN	Enzyme (other)	yes	2.3.1.39	Thioesterase, Ac_transferase_dom_sf, Ppantetheine_attach_site
ACTA2	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
CASP10	Enzyme (other)	yes	3.4.22.63	Pept_C14_p20, DED_dom, Pept_C14_p10
SLC9C2	Other/Unknown	no		cNMP-bd_dom, Cation/H_exchanger_TM, RmlC-like_jellyroll
FAS-AS1	Other/Unknown	no
ITK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
MYOC	Other/Unknown	no		Olfac-like_dom, Olfactomedin-like_domain

Expression context

Cohort genes with no expression data: 1.

8 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)	8
unknown	1

Top tissues across cohort

Tissue	Cohort genes
granulocyte	3
blood	2
left ovary	1
rectum	1
right ovary	1
lymph node	1
endometrium epithelium	1
right hemisphere of cerebellum	1
skin of abdomen	1
blood vessel layer	1
cauda epididymis	1
saphenous vein	1
colonic epithelium	1
monocyte	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1
right uterine tube	1
thymus	1
calcaneal tendon	1
esophagogastric junction muscularis propria	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FAS	280	ubiquitous	marker	rectum, left ovary, right ovary
FASLG	118	tissue_specific	marker	granulocyte, blood, lymph node
FASN	273	ubiquitous	marker	right hemisphere of cerebellum, endometrium epithelium, skin of abdomen
ACTA2	289	ubiquitous	marker	cauda epididymis, blood vessel layer, saphenous vein
CASP10	206	ubiquitous	marker	colonic epithelium, granulocyte, monocyte
SLC9C2	142	tissue_specific	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, right testis
FAS-AS1
ITK	198	broad	marker	granulocyte, thymus, blood
MYOC	201	tissue_specific	marker	calcaneal tendon, mucosa of stomach, esophagogastric junction muscularis propria

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FASN	6,551
FASLG	4,373
FAS	3,314
ITK	2,670
MYOC	1,272
CASP10	1,242
ACTA2	774
SLC9C2	578
FAS-AS1	0

Intra-cohort edges

A	B	Sources
ACTA2	MYOC	biogrid_interaction
CASP10	FAS	intact, string_interaction
CASP10	FASLG	biogrid_interaction, string_interaction
FAS	FASLG	intact, string_interaction
FASLG	ITK	intact

Structural data

PDB: 5 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ITK	Q08881	37
FASN	P49327	34
MYOC	Q99972	24
FAS	P25445	7
FASLG	P48023	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACTA2	P62736	95.43
SLC9C2	Q5TAH2	77.79
CASP10	Q92851	69.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 52. Enrichment computed across 9 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×	7e-08	FAS, FASLG, CASP10
Regulation by c-FLIP	2	296.6×	2e-04	FAS, FASLG
CASP8 activity is inhibited	2	296.6×	2e-04	FAS, FASLG
Dimerization of procaspase-8	2	296.6×	2e-04	FAS, FASLG
Caspase activation via Death Receptors in the presence of ligand	2	217.5×	4e-04	FAS, FASLG
RIPK1-mediated regulated necrosis	2	130.5×	8e-04	FAS, FASLG
TRAIL signaling	1	203.9×	0.032	CASP10
ChREBP activates metabolic gene expression	1	181.3×	0.032	FASN
NR1H2 & NR1H3 regulate gene expression linked to lipogenesis	1	163.1×	0.032	FASN
TP53 Regulates Transcription of Caspase Activators and Caspases	1	135.9×	0.032	CASP10
TP53 Regulates Transcription of Death Receptors and Ligands	1	135.9×	0.032	FAS
Regulation of CDH1 Function	1	135.9×	0.032	ACTA2
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	1	125.5×	0.032	CASP10
Vitamin B5 (pantothenate) metabolism	1	108.8×	0.033	FASN
FOXO-mediated transcription of cell death genes	1	102.0×	0.033	FASLG
NOTCH4 Intracellular Domain Regulates Transcription	1	81.6×	0.033	ACTA2
TP53 Regulates Transcription of Cell Death Genes	1	77.7×	0.033	CASP10
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	77.7×	0.033	ACTA2
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	74.2×	0.033	FASLG
TCR signaling	1	70.9×	0.033	ITK
Signaling by NOTCH4	1	70.9×	0.033	ACTA2
Immune System	3	5.6×	0.033	FASLG, CASP10, ITK
Fatty acyl-CoA biosynthesis	1	62.8×	0.036	FASN
TNFs bind their physiological receptors	1	56.3×	0.038	FASLG
FCERI mediated Ca+2 mobilization	1	51.0×	0.040	ITK
Generation of second messenger molecules	1	49.4×	0.040	ITK
Dengue Virus Genome Translation and Replication	1	45.3×	0.042	FASN
Formation of the dystrophin-glycoprotein complex (DGC)	1	44.1×	0.042	ACTA2
Fc epsilon receptor (FCERI) signaling	1	38.8×	0.044	ITK
Smooth Muscle Contraction	1	37.9×	0.044	ACTA2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 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	526.6×	6e-04	FAS, FASLG
skeletal muscle hypertrophy	1	2106.5×	0.007	MYOC
positive regulation of hepatic stellate cell contraction	1	2106.5×	0.007	ACTA2
positive regulation of phosphatidylserine exposure on apoptotic cell surface	1	2106.5×	0.007	FASLG
extrinsic apoptotic signaling pathway via death domain receptors	2	100.3×	0.007	FAS, FASLG
extrinsic apoptotic signaling pathway	2	76.6×	0.007	FAS, FASLG
positive regulation of neuron apoptotic process	2	68.0×	0.007	FASLG, CASP10
inflammatory cell apoptotic process	1	1053.2×	0.009	FASLG
positive regulation of hepatic stellate cell migration	1	1053.2×	0.009	ACTA2
release of sequestered calcium ion into cytosol by endoplasmic reticulum	1	1053.2×	0.009	FASLG
signal transduction	4	8.0×	0.009	FAS, FASLG, ITK, MYOC
Fas signaling pathway	1	702.2×	0.010	FAS
retinal cell programmed cell death	1	702.2×	0.010	FASLG
juxtaglomerular apparatus development	1	702.2×	0.010	ACTA2
NK T cell differentiation	1	526.6×	0.011	ITK
glomerular mesangial cell development	1	526.6×	0.011	ACTA2
osteoblast differentiation	2	30.3×	0.011	FASN, MYOC
vascular associated smooth muscle contraction	1	421.3×	0.011	ACTA2
cellular response to hyperoxia	1	421.3×	0.011	FAS
mesenchyme migration	1	421.3×	0.011	ACTA2
apoptotic process	3	10.8×	0.011	FAS, FASLG, CASP10
positive regulation of hepatic stellate cell activation	1	351.1×	0.013	ACTA2
acetyl-CoA metabolic process	1	300.9×	0.013	FASN
activation-induced cell death of T cells	1	300.9×	0.013	FAS
clustering of voltage-gated sodium channels	1	300.9×	0.013	MYOC
gamma-delta T cell activation	1	263.3×	0.014	ITK
ether lipid biosynthetic process	1	234.1×	0.014	FASN
neutrophil differentiation	1	234.1×	0.014	FASN
regulation of stress-activated MAPK cascade	1	234.1×	0.014	FAS
host-mediated perturbation of viral process	1	234.1×	0.014	FASN

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 7

Druggability breadth: 6 of 9 evidence-associated genes (67%) 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
ITK	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ITK	39	4
FASN	8	4
FAS	0	0
FASLG	0	0
ACTA2	0	0
CASP10	0	0
SLC9C2	0	0
FAS-AS1	0	0
MYOC	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
FEDRATINIB	4	ITK
AXITINIB	4	ITK
IBRUTINIB	4	ITK
BOSUTINIB	4	ITK
ACALABRUTINIB	4	ITK
ZANUBRUTINIB	4	ITK
RITLECITINIB	4	ITK
NINTEDANIB	4	ITK
SUNITINIB	4	ITK
DASATINIB	4	ITK
QUIZARTINIB	4	ITK
CRIZOTINIB	4	ITK
EPIGALOCATECHIN GALLATE	3	FASN
CANERTINIB	3	ITK
EVOBRUTINIB	3	ITK
REMIBRUTINIB	3	ITK
DOVITINIB	3	ITK
LESTAURTINIB	3	ITK
LUTEOLIN	2	FASN
DENIFANSTAT	2	FASN
FORETINIB	2	ITK
TANDUTINIB	2	ITK
SU-014813	2	ITK
REBASTINIB	2	ITK
CENISERTIB	2	ITK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
ITK	563	Binding:547, Functional:10, ADMET:6
FASN	142	Binding:136, Functional:6
CASP10	22	Binding:21, Functional:1
FAS	8	Binding:8
MYOC	4	Binding:4
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
ITK	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
FASN	142
ITK	563

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; 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
FEDRATINIB	4	ITK
AXITINIB	4	ITK
IBRUTINIB	4	ITK
BOSUTINIB	4	ITK
ACALABRUTINIB	4	ITK
ZANUBRUTINIB	4	ITK
RITLECITINIB	4	ITK
NINTEDANIB	4	ITK
SUNITINIB	4	ITK
DASATINIB	4	ITK
QUIZARTINIB	4	ITK
CRIZOTINIB	4	ITK
EPIGALOCATECHIN GALLATE	3	FASN
CANERTINIB	3	ITK
EVOBRUTINIB	3	ITK
REMIBRUTINIB	3	ITK
DOVITINIB	3	ITK
LESTAURTINIB	3	ITK
LUTEOLIN	2	FASN
DENIFANSTAT	2	FASN
FORETINIB	2	ITK
TANDUTINIB	2	ITK
SU-014813	2	ITK
REBASTINIB	2	ITK
CENISERTIB	2	ITK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	FASN, ITK
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	6	FAS, FASLG, ACTA2, SLC9C2, FAS-AS1, MYOC

Undrugged target profiles

7 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	—
ACTA2	0	—
CASP10	22	—
SLC9C2	0	—
FAS-AS1	0	—
MYOC	4	—

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