autoimmune lymphoproliferative syndrome type 2A

Summary

autoimmune lymphoproliferative syndrome type 2A (MONDO:0011383) is a disease caused by CASP10 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CASP10 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 572

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autoimmune lymphoproliferative syndrome type 2A
Mondo ID	MONDO:0011383
MeSH	C565833
OMIM	603909
DOID	DOID:0110115
NCIT	C39576
UMLS	C1858968
MedGen	349065
GARD	0015361
Is cancer (heuristic)	no

Also known as: ALPS-CASP10 · ALPS2A · autoimmune lymphoproliferative syndrome caused by mutation in CASP10 · autoimmune lymphoproliferative syndrome, type II · autoimmune lymphoproliferative syndrome, type IIA · autoimmune lymphoproliferative syndrome-CASP10 variant · CASP10 autoimmune lymphoproliferative syndrome · type 2 ALPS · type 2 autoimmune lymphoproliferative syndrome

Data availability: 572 ClinVar variants · 2 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 2A

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

572 retrieved; paginated sample, class counts are floors:

356 uncertain significance, 145 likely benign, 44 benign, 17 conflicting classifications of pathogenicity, 9 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1685600	NM_032977.4(CASP10):c.1504del (p.Gln502fs)	CASP10	Pathogenic	criteria provided, single submitter
1008364	NM_032977.4(CASP10):c.1453G>A (p.Asp485Asn)	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1338169	NM_032977.4(CASP10):c.1249C>T (p.Leu417=)	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2418856	NM_032977.4(CASP10):c.387_388del (p.Asn130fs)	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
333415	NM_032977.4(CASP10):c.20A>G (p.His7Arg)	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
333416	NM_032977.4(CASP10):c.49A>G (p.Lys17Glu)	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
333424	NM_032977.4(CASP10):c.534A>G (p.Val178=)	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
333431	NM_032977.4(CASP10):c.879C>A (p.Ser293Arg)	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
333435	NM_032977.4(CASP10):c.1216A>T (p.Ile406Leu)	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
333440	NM_032977.4(CASP10):c.1466G>A (p.Arg489Gln)	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
333441	NM_032977.4(CASP10):c.1502C>T (p.Pro501Leu)	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
535760	NM_032977.4(CASP10):c.1202_1208del (p.Cys401fs)	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
643723	NM_032977.4(CASP10):c.1321G>A (p.Ala441Thr)	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
714082	NM_032977.4(CASP10):c.81T>C (p.Ile27=)	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
801851	NM_032977.4(CASP10):c.-8+5G>A	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895421	NM_032977.4(CASP10):c.442-14T>G	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897314	NM_032977.4(CASP10):c.721G>A (p.Gly241Ser)	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897316	NM_032977.4(CASP10):c.913A>G (p.Lys305Glu)	CASP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007405	NM_032977.4(CASP10):c.844C>A (p.His282Asn)	CASP10	Uncertain significance	criteria provided, single submitter
1011666	NM_032977.4(CASP10):c.62G>A (p.Arg21His)	CASP10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1014291	NM_032977.4(CASP10):c.1285A>G (p.Ser429Gly)	CASP10	Uncertain significance	criteria provided, single submitter
1014752	NM_032977.4(CASP10):c.258A>G (p.Ile86Met)	CASP10	Uncertain significance	criteria provided, single submitter
1016231	NM_032977.4(CASP10):c.530T>G (p.Val177Gly)	CASP10	Uncertain significance	criteria provided, single submitter
1018382	NM_032977.4(CASP10):c.1558C>T (p.Leu520Phe)	CASP10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1021078	NM_032977.4(CASP10):c.548G>T (p.Arg183Ile)	CASP10	Uncertain significance	criteria provided, single submitter
1023122	NM_032977.4(CASP10):c.685-2A>G	CASP10	Uncertain significance	criteria provided, single submitter
1031528	NM_032977.4(CASP10):c.1465C>T (p.Arg489Ter)	CASP10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1039059	NM_032977.4(CASP10):c.244CTC[1] (p.Leu83del)	CASP10	Uncertain significance	criteria provided, single submitter
1042593	NM_032977.4(CASP10):c.922+5G>A	CASP10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1044093	NM_032977.4(CASP10):c.760A>G (p.Arg254Gly)	CASP10	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
CASP10	Strong	Autosomal dominant	autoimmune lymphoproliferative syndrome type 2A	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CASP10	Orphanet:3261	Autoimmune lymphoproliferative syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CASP10	HGNC:1500	ENSG00000003400	Q92851	Caspase-10	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CASP10	Caspase-10	Involved in the activation cascade of caspases responsible for apoptosis execution.

Protein-family classification

Druggable: 1 · 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)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CASP10	Enzyme (other)	yes	3.4.22.63	Pept_C14_p20, DED_dom, Pept_C14_p10

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	1
granulocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CASP10	206	ubiquitous	marker	colonic epithelium, granulocyte, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CASP10	1,242

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CASP10	Q92851	69.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 1 evidence-associated genes (1 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 1 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	1	2284.0×	0.004	CASP10
TRAIL signaling	1	1427.5×	0.004	CASP10
TP53 Regulates Transcription of Caspase Activators and Caspases	1	951.7×	0.004	CASP10
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	1	878.5×	0.004	CASP10
TP53 Regulates Transcription of Cell Death Genes	1	543.8×	0.005	CASP10
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1	253.8×	0.009	CASP10
Death Receptor Signaling	1	139.3×	0.014	CASP10
Transcriptional Regulation by TP53	1	62.1×	0.028	CASP10
Innate Immune System	1	25.5×	0.061	CASP10
RNA Polymerase II Transcription	1	22.5×	0.062	CASP10
Gene expression (Transcription)	1	17.8×	0.071	CASP10
Generic Transcription Pathway	1	15.1×	0.077	CASP10
Immune System	1	13.0×	0.083	CASP10
Signal Transduction	1	10.2×	0.098	CASP10

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 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	1	842.6×	0.007	CASP10
positive regulation of neuron apoptotic process	1	271.8×	0.011	CASP10
protein maturation	1	163.6×	0.012	CASP10
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.021	CASP10
proteolysis	1	34.2×	0.035	CASP10
apoptotic process	1	28.7×	0.035	CASP10

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CASP10	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CASP10	22	Binding:21, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CASP10	3.4.22.63	caspase-10

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CASP10	22	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.