autoimmune lymphoproliferative syndrome type 2B

Summary

autoimmune lymphoproliferative syndrome type 2B (MONDO:0011804) is a disease caused by CASP8 (GenCC Strong), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CASP8 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 339

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Identifiers

Disease identifiers

Field	Value
Canonical name	autoimmune lymphoproliferative syndrome type 2B
Mondo ID	MONDO:0011804
OMIM	607271
Orphanet	275517
DOID	DOID:0110116
SNOMED CT	722290008
UMLS	C1846545
MedGen	339548
GARD	0009796
Is cancer (heuristic)	no

Also known as: ALPS2B · autoimmune lymphoproliferative syndrome caused by mutation in CASP8 · autoimmune lymphoproliferative syndrome, type IIB · CASP8 autoimmune lymphoproliferative syndrome · caspase 8 deficiency · caspase 8 deficiency syndrome · caspase-8 deficiency · CEDS

Data availability: 339 ClinVar variants · 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 type 2B

Related subtypes (8): autoimmune lymphoproliferative syndrome type 1, autoimmune lymphoproliferative syndrome type 2A, 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

339 retrieved; paginated sample, class counts are floors:

157 uncertain significance, 127 likely benign, 20 pathogenic, 13 benign, 11 conflicting classifications of pathogenicity, 5 likely pathogenic, 5 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
659600	NC_000002.12:g.(?201228913)(201286614_?)del	CASP10	Pathogenic	criteria provided, single submitter
1394714	NM_001372051.1(CASP8):c.879T>A (p.Tyr293Ter)	CASP8	Pathogenic	criteria provided, single submitter
1935186	NM_001372051.1(CASP8):c.306-1930dup	CASP8	Pathogenic	criteria provided, single submitter
2037856	NM_001372051.1(CASP8):c.679C>T (p.Gln227Ter)	CASP8	Pathogenic	criteria provided, single submitter
2072614	NM_001372051.1(CASP8):c.306-1954_306-1953del	CASP8	Pathogenic	criteria provided, single submitter
2130976	NM_001372051.1(CASP8):c.429_430insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGGAAGCTCCCAAGATGACTACCTCCAGCCTCTGGCCACAGGGAACCTTCTTCATATCCCACAAGCAAAGGAGCTGGATATTTTC (p.Phe143_Ile144insPhePhePhePhePhePheXaaXaaXaaXaaGlySerSerGlnAspAspTyrLeuGlnProLeuAlaThrGlyAsnLeuLeuHisIleProGlnAlaLysGluLeuAspIlePhe)	CASP8	Pathogenic	criteria provided, single submitter
2186059	NM_001372051.1(CASP8):c.983dup (p.Gln329fs)	CASP8	Pathogenic	criteria provided, single submitter
2762094	NM_001372051.1(CASP8):c.492_493del (p.Ala165fs)	CASP8	Pathogenic	criteria provided, single submitter
2790366	NM_001372051.1(CASP8):c.306-1976del	CASP8	Pathogenic	criteria provided, single submitter
2885998	NM_001372051.1(CASP8):c.306-1978G>T	CASP8	Pathogenic	criteria provided, single submitter
2896117	NM_001372051.1(CASP8):c.918del (p.Asn306fs)	CASP8	Pathogenic	criteria provided, single submitter
3247245	NC_000002.11:g.(?202131210)(202151317_?)del	CASP8	Pathogenic	criteria provided, single submitter
3247246	NC_000002.11:g.(?202131210)(202134348_?)del	CASP8	Pathogenic	criteria provided, single submitter
4812021	NM_001372051.1(CASP8):c.613dup (p.Val205fs)	CASP8	Pathogenic	criteria provided, single submitter
4847516	NM_001372051.1(CASP8):c.691A>T (p.Lys231Ter)	CASP8	Pathogenic	criteria provided, single submitter
631840	NM_001372051.1(CASP8):c.1165C>T (p.Gln389Ter)	CASP8	Pathogenic	criteria provided, single submitter
7760	NM_001372051.1(CASP8):c.742C>T (p.Arg248Trp)	CASP8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
946113	NM_001372051.1(CASP8):c.202C>T (p.Arg68Ter)	CASP8	Pathogenic	criteria provided, single submitter
968654	NM_001372051.1(CASP8):c.306-1949_306-1947delinsC	CASP8	Pathogenic	criteria provided, single submitter
973624	NM_001372051.1(CASP8):c.1303C>T (p.Arg435Ter)	CASP8	Pathogenic	no assertion criteria provided
1456057	NC_000002.11:g.(?201943606)(204824322_?)del	STRADB	Pathogenic	criteria provided, single submitter
1068184	NM_001372051.1(CASP8):c.306-1910G>A	CASP8	Likely pathogenic	criteria provided, single submitter
1516540	NM_001372051.1(CASP8):c.411+1G>C	CASP8	Likely pathogenic	criteria provided, single submitter
3652746	NM_001372051.1(CASP8):c.306-1G>A	CASP8	Likely pathogenic	criteria provided, single submitter
4707109	NM_001372051.1(CASP8):c.306-2007G>T	CASP8	Likely pathogenic	criteria provided, single submitter
830621	NC_000002.12:g.(?201276807)(201276988_?)dup	CASP8	Likely pathogenic	criteria provided, single submitter
1109901	NM_001372051.1(CASP8):c.1128G>C (p.Glu376Asp)	CASP8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1355954	NM_001372051.1(CASP8):c.306-1981del	CASP8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2168995	NM_001372051.1(CASP8):c.306-1990A>G	CASP8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
333503	NM_001372051.1(CASP8):c.843C>A (p.Ile281=)	CASP8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
CASP8	Strong	Autosomal recessive	autoimmune lymphoproliferative syndrome type 2B	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CASP8	Orphanet:210159	Adult hepatocellular carcinoma
CASP8	Orphanet:275517	Autoimmune lymphoproliferative syndrome-recurrent viral infections due to CASP8 deficiency
CASP10	Orphanet:3261	Autoimmune lymphoproliferative syndrome
CD28	Orphanet:2584	Classic mycosis fungoides
CD28	Orphanet:3162	Sézary 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
CASP8	HGNC:1509	ENSG00000064012	Q14790	Caspase-8	gencc,clinvar
STRADB	HGNC:13205	ENSG00000082146	Q9C0K7	STE20-related kinase adapter protein beta	clinvar
CASP10	HGNC:1500	ENSG00000003400	Q92851	Caspase-10	clinvar
CD28	HGNC:1653	ENSG00000178562	P10747	T-cell-specific surface glycoprotein CD28	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CASP8	Caspase-8	Thiol protease that plays a key role in programmed cell death by acting as a molecular switch for apoptosis, necroptosis and pyroptosis, and is required to prevent tissue damage during embryonic development and adulthood.
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.
CASP10	Caspase-10	Involved in the activation cascade of caspases responsible for apoptosis execution.
CD28	T-cell-specific surface glycoprotein CD28	Receptor that plays a role in T-cell activation, proliferation, survival and the maintenance of immune homeostasis.

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
Enzyme (other)	2	6.0×	0.112
Antibody/Immunoglobulin	1	7.3×	0.137
Kinase	1	6.9×	0.137

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CASP8	Enzyme (other)	yes	3.4.22.61	Pept_C14_p20, DED_dom, Pept_C14_p10
STRADB	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, STRAD_A/B-like
CASP10	Enzyme (other)	yes	3.4.22.63	Pept_C14_p20, DED_dom, Pept_C14_p10
CD28	Antibody/Immunoglobulin	yes		CD28, Ig_V-set, Ig-like_fold

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
monocyte	2
leukocyte	1
mononuclear cell	1
adrenal tissue	1
right adrenal gland	1
right adrenal gland cortex	1
colonic epithelium	1
granulocyte	1
blood	1
lymph node	1
vermiform appendix	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CASP8	252	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
STRADB	140	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
CASP10	206	ubiquitous	marker	colonic epithelium, granulocyte, monocyte
CD28	154	broad	marker	lymph node, vermiform appendix, blood

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CASP8	5,040
CD28	2,958
CASP10	1,242
STRADB	882

Intra-cohort edges

A	B	Sources
CASP10	CASP8	biogrid_interaction, intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CASP8	Q14790	36
CD28	P10747	10

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
STRADB	Q9C0K7	74.39
CASP10	Q92851	69.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 86. 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
FasL/ CD95L signaling	2	1142.0×	8e-05	CASP8, CASP10
TRAIL signaling	2	713.8×	1e-04	CASP8, CASP10
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	2	439.2×	2e-04	CASP8, CASP10
DDX58/IFIH1-mediated induction of interferon-alpha/beta	2	126.9×	0.002	CASP8, CASP10
Signal Transduction	4	10.2×	0.002	CASP8, STRADB, CASP10, CD28
Death Receptor Signaling	2	69.6×	0.004	CASP8, CASP10
Nef mediated downregulation of CD28 cell surface expression	1	1427.5×	0.009	CD28
Activation, myristolyation of BID and translocation to mitochondria	1	713.8×	0.013	CASP8
Microbial modulation of RIPK1-mediated regulated necrosis	1	713.8×	0.013	CASP8
CLEC7A/inflammasome pathway	1	475.8×	0.014	CASP8
TLR3-mediated TICAM1-dependent programmed cell death	1	475.8×	0.014	CASP8
Defective RIPK1-mediated regulated necrosis	1	475.8×	0.014	CASP8
Immune System	3	9.7×	0.014	CASP8, CASP10, CD28
Caspase activation via extrinsic apoptotic signalling pathway	1	356.9×	0.017	CASP8
TRIF-mediated programmed cell death	1	317.2×	0.018	CASP8
Regulation by c-FLIP	1	259.6×	0.018	CASP8
CASP8 activity is inhibited	1	259.6×	0.018	CASP8
Dimerization of procaspase-8	1	259.6×	0.018	CASP8
Caspase-mediated cleavage of cytoskeletal proteins	1	237.9×	0.018	CASP8
TP53 Regulates Transcription of Caspase Activators and Caspases	1	237.9×	0.018	CASP10
CD28 dependent Vav1 pathway	1	219.6×	0.019	CD28
Caspase activation via Death Receptors in the presence of ligand	1	190.3×	0.020	CASP8
Regulated Necrosis	1	178.4×	0.020	CASP8
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1	158.6×	0.020	CD28
The role of Nef in HIV-1 replication and disease pathogenesis	1	158.6×	0.020	CD28
Diseases of programmed cell death	1	158.6×	0.020	CASP8
Regulation of NF-kappa B signaling	1	158.6×	0.020	CASP8
TP53 Regulates Transcription of Cell Death Genes	1	135.9×	0.023	CASP10
Apoptotic cleavage of cellular proteins	1	119.0×	0.023	CASP8
Apoptotic execution phase	1	119.0×	0.023	CASP8

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
positive regulation of execution phase of apoptosis	2	421.3×	6e-04	CASP8, CASP10
positive regulation of neuron apoptotic process	2	135.9×	0.002	CASP8, CASP10
T cell activation	2	129.6×	0.002	CASP8, CD28
apoptotic signaling pathway	2	112.3×	0.002	CASP8, CD28
protein maturation	2	81.8×	0.003	CASP8, CASP10
positive regulation of inflammatory response to antigenic stimulus	1	1404.3×	0.007	CD28
syncytiotrophoblast cell differentiation involved in labyrinthine layer development	1	1404.3×	0.007	CASP8
positive regulation of canonical NF-kappaB signal transduction	2	36.3×	0.010	CASP8, CASP10
response to anesthetic	1	702.2×	0.010	CASP8
response to cobalt ion	1	601.9×	0.010	CASP8
regulatory T cell differentiation	1	526.6×	0.010	CD28
CD4-positive, alpha-beta T cell proliferation	1	468.1×	0.010	CD28
TRAIL-activated apoptotic signaling pathway	1	468.1×	0.010	CASP8
regulation of regulatory T cell differentiation	1	468.1×	0.010	CD28
positive regulation of CD4-positive, alpha-beta T cell proliferation	1	421.3×	0.010	CD28
activation of protein kinase activity	1	383.0×	0.010	STRADB
positive regulation of isotype switching to IgG isotypes	1	383.0×	0.010	CD28
self proteolysis	1	383.0×	0.010	CASP8
negative thymic T cell selection	1	351.1×	0.011	CD28
positive regulation of macrophage differentiation	1	300.9×	0.012	CASP8
negative regulation of necroptotic process	1	247.8×	0.014	CASP8
positive regulation of proteolysis	1	200.6×	0.015	CASP8
positive regulation of T cell receptor signaling pathway	1	191.5×	0.015	CD28
execution phase of apoptosis	1	191.5×	0.015	CASP8
proteolysis	2	17.1×	0.015	CASP8, CASP10
regulation of tumor necrosis factor-mediated signaling pathway	1	175.5×	0.015	CASP8
regulation of innate immune response	1	162.0×	0.015	CASP8
response to tumor necrosis factor	1	156.0×	0.015	CASP8
natural killer cell activation	1	145.3×	0.015	CASP8
positive regulation of viral genome replication	1	145.3×	0.015	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
CASP8	PRIMAQUINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CASP8	2	4
STRADB	0	0
CASP10	0	0
CD28	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PRIMAQUINE PHOSPHATE	4	CASP8
PRALNACASAN	2	CASP8

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CASP8	116	Binding:106, Functional:10
CASP10	22	Binding:21, Functional:1
STRADB	20	Binding:20
CD28	1	Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CASP8	3.4.22.61	caspase-8
CASP10	3.4.22.63	caspase-10

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CASP8	116

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

2 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)
PRIMAQUINE PHOSPHATE	4	CASP8
PRALNACASAN	2	CASP8

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CASP8
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	CD28
D	Druggable family + AlphaFold only, no drug	2	STRADB, CASP10
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)
CASP10	22	CASP8
STRADB	20	—
CD28	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.