Wiskott-Aldrich syndrome 2

Summary

Wiskott-Aldrich syndrome 2 (MONDO:0013779) is a disease caused by WIPF1 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: WIPF1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 311

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Wiskott-Aldrich syndrome 2
Mondo ID	MONDO:0013779
OMIM	277970, 614493
NCIT	C176820
UMLS	C3281001
MedGen	482631
GARD	0015809
Is cancer (heuristic)	no

Also known as: WAS2 · WIPF1 Wiskott-Aldrich syndrome · Wiskott-Aldrich syndrome 2 · Wiskott-Aldrich syndrome caused by mutation in WIPF1 · Wiskott-Aldrich syndrome type 2

Data availability: 311 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › Wiskott-Aldrich syndrome 2

Related subtypes (94): B cell deficiency, T-cell immunodeficiency, complement deficiency, myalgic encephalomeyelitis/chronic fatigue syndrome, hypoproteinemia, hypercatabolic, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, autosomal dominant form, immunodeficiency due to CD25 deficiency, immunodeficiency 67, primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency, immunodeficiency 35, pyogenic bacterial infections due to MyD88 deficiency, lymphoproliferative syndrome 1, FADD-related immunodeficiency, immunodeficiency 31B, cryptosporidiosis-chronic cholangitis-liver disease syndrome, idiopathic CD4 lymphocytopenia, immunodeficiency 23, DOCK2 deficiency, immunodeficiency 45, TFRC-related combined immunodeficiency, combined immunodeficiency, autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome, immunodeficiency due to selective anti-polysaccharide antibody deficiency, immunodeficiency 57, immunodeficiency 14b, autosomal recessive, immunodeficiency 98 with autoinflammation, X-linked, immunodeficiency 102, immunodeficiency 74, COVID-19-related, X-linked, immunodeficiency 66, immunodeficiency 80 with or without congenital cardiomyopathy, immunodeficiency 81, immunodeficiency 82 with systemic inflammation, immunodeficiency 84, immunodeficiency 85 and autoimmunity, immunodeficiency 86, immunodeficiency 87 and autoimmunity, immunodeficiency 88, immunodeficiency 89 and autoimmunity, immunodeficiency 91 and hyperinflammation, immunodeficiency 92, immunodeficiency 93 and hypertrophic cardiomyopathy, immunodeficiency 95, immunodeficiency 96, immunodeficiency 97 with autoinflammation, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, immunodeficiency 101 (varicella zoster virus-specific), immunodeficiency 75, immunodeficiency 76, immunodeficiency 106, susceptibility to viral infections, immunodeficiency 78 with autoimmunity and developmental delay, immunodeficiency 77, immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, immunodeficiency 15a, immunodeficiency 60, immunodeficiency 62, immunodeficiency 63 with lymphoproliferation and autoimmunity, immunodeficiency 64, immunodeficiency 65, susceptibility to viral infections, immunodeficiency 69, immunodeficiency 70, immunodeficiency 72 with autoinflammation, GATA2 deficiency with susceptibility to MDS/AML, Shwachman-Diamond syndrome 1, immunodeficiency 53, immunodeficiency 11b with atopic dermatitis, IKBKG-related immunodeficiency with or without ectodermal dysplasia, FNIP1-associated syndrome, FASLG-related immunodeficiency, TNFRSF9-related immunodeficiency, DNAJC21-related Shwachman Diamond syndrome, IRF4-related immune disorder, PTEN harmartoma tumor syndrome with immune disorder, primary immunodeficiency due to calcium channel deficiency, chronic mucocutaneous candidiasis and connective tissue disease due to JNK1 haploinsufficiency, immune deficiency due to impaired neutrophil phagocytosis and migration, hatipoglu immunodeficiency syndrome, immunodeficiency 112, immunodeficiency 113 with autoimmunity and autoinflammation, immunodeficiency 114, folate-responsive, immunodeficiency 115 with autoinflammation, immunodeficiency 117, immunodeficiency 118, immunodeficiency 119, immunodeficiency 121 with autoinflammation, immunodeficiency 122, immunodeficiency 123 with HPV-related verrucosis, immunodeficiency 125, immunodeficiency 126, susceptibility to, immunodeficiency 127, immunodeficiency 128, immunodeficiency 132b, immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, immunodeficiency 134 (Epstein-Barr virus-specific)

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

311 retrieved; paginated sample, class counts are floors:

151 likely benign, 136 uncertain significance, 10 benign, 6 pathogenic, 5 conflicting classifications of pathogenicity, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2821077	NM_001375834.1(WIPF1):c.587C>G (p.Ser196Ter)	WIPF1	Pathogenic	criteria provided, single submitter
30266	NM_001375834.1(WIPF1):c.1301C>G (p.Ser434Ter)	WIPF1	Pathogenic	no assertion criteria provided
3691481	NM_001375834.1(WIPF1):c.373C>T (p.Arg125Ter)	WIPF1	Pathogenic	criteria provided, single submitter
3728324	NM_001375834.1(WIPF1):c.284del (p.Gly95fs)	WIPF1	Pathogenic	criteria provided, single submitter
4732404	NM_001375834.1(WIPF1):c.420del (p.Ser142fs)	WIPF1	Pathogenic	criteria provided, single submitter
976496	NM_001375834.1(WIPF1):c.709C>T (p.Gln237Ter)	WIPF1	Pathogenic	no assertion criteria provided
252518	NM_001375834.1(WIPF1):c.208G>A (p.Gly70Ser)	WIPF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
472919	NM_001375834.1(WIPF1):c.1037C>T (p.Pro346Leu)	WIPF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
540145	NM_001375834.1(WIPF1):c.1380C>T (p.Ser460=)	WIPF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
661880	NM_001375834.1(WIPF1):c.473G>A (p.Arg158Lys)	WIPF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
846396	NM_001375834.1(WIPF1):c.122G>A (p.Ser41Asn)	WIPF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2423598	NC_000002.11:g.(?175427275)(175629122_?)dup	CHRNA1	Uncertain significance	criteria provided, single submitter
646952	NC_000002.11:g.(?175427255)(175450321_?)dup	LOC129935136	Uncertain significance	criteria provided, single submitter
1002230	NM_001375834.1(WIPF1):c.979G>A (p.Gly327Ser)	WIPF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1004746	NM_001375834.1(WIPF1):c.413C>T (p.Ala138Val)	WIPF1	Uncertain significance	criteria provided, single submitter
1004966	NM_001375834.1(WIPF1):c.1078C>T (p.Pro360Ser)	WIPF1	Uncertain significance	criteria provided, single submitter
1006773	NM_001375834.1(WIPF1):c.61G>A (p.Glu21Lys)	WIPF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1006851	NM_001375834.1(WIPF1):c.1468C>T (p.Arg490Ter)	WIPF1	Uncertain significance	criteria provided, single submitter
1023025	NM_001375834.1(WIPF1):c.419C>T (p.Pro140Leu)	WIPF1	Uncertain significance	criteria provided, single submitter
1024739	NM_001375834.1(WIPF1):c.698G>T (p.Gly233Val)	WIPF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1038152	NM_001375834.1(WIPF1):c.1100C>T (p.Pro367Leu)	WIPF1	Uncertain significance	criteria provided, single submitter
1041875	NM_001375834.1(WIPF1):c.1233G>T (p.Arg411Ser)	WIPF1	Uncertain significance	criteria provided, single submitter
1041974	NM_001375834.1(WIPF1):c.509C>G (p.Pro170Arg)	WIPF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1051683	NM_001375834.1(WIPF1):c.1094C>T (p.Pro365Leu)	WIPF1	Uncertain significance	criteria provided, single submitter
1054457	NM_001375834.1(WIPF1):c.26C>T (p.Pro9Leu)	WIPF1	Uncertain significance	criteria provided, single submitter
1054813	NM_001375834.1(WIPF1):c.1481G>A (p.Gly494Asp)	WIPF1	Uncertain significance	criteria provided, single submitter
1057935	NM_001375834.1(WIPF1):c.707G>C (p.Arg236Pro)	WIPF1	Uncertain significance	criteria provided, single submitter
1059191	NM_001375834.1(WIPF1):c.595C>T (p.His199Tyr)	WIPF1	Uncertain significance	criteria provided, single submitter
1059501	NM_001375834.1(WIPF1):c.668C>G (p.Pro223Arg)	WIPF1	Uncertain significance	criteria provided, single submitter
1061748	NM_001375834.1(WIPF1):c.613C>A (p.Pro205Thr)	WIPF1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · 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
WIPF1	Strong	Autosomal recessive	Wiskott-Aldrich syndrome 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WIPF1	Orphanet:714493	Congenital thrombocytopenia-recurrent infections syndrome due to WIP deficiency
CHRNA1	Orphanet:33108	Lethal multiple pterygium syndrome
CHRNA1	Orphanet:98913	Postsynaptic congenital myasthenic syndrome

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WIPF1	HGNC:12736	ENSG00000115935	O43516	WAS/WASL-interacting protein family member 1	gencc,clinvar
CHRNA1	HGNC:1955	ENSG00000138435	P02708	Acetylcholine receptor subunit alpha	clinvar
WIPF1-AS1	HGNC:40613	ENSG00000237798		WIPF1 and CHRNA1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WIPF1	WAS/WASL-interacting protein family member 1	Plays a role in the reorganization of the actin cytoskeleton.
CHRNA1	Acetylcholine receptor subunit alpha	Upon acetylcholine binding, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WIPF1	Other/Unknown	no		WH2_dom, PH-like_dom_sf, WAS/WASL-interacting_domain
CHRNA1	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
WIPF1-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
leukocyte	1
monocyte	1
gastrocnemius	1
gluteal muscle	1
muscle of leg	1
bone marrow cell	1
granulocyte	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WIPF1	284	ubiquitous	marker	blood, monocyte, leukocyte
CHRNA1	149	broad	marker	gastrocnemius, gluteal muscle, muscle of leg
WIPF1-AS1	114		yes	male germ line stem cell (sensu Vertebrata) in testis, bone marrow cell, granulocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WIPF1	1,600
CHRNA1	1,058
WIPF1-AS1	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHRNA1	P02708	15
WIPF1	O43516	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Highly calcium permeable nicotinic acetylcholine receptors	1	634.4×	0.006	CHRNA1
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors	1	519.1×	0.006	CHRNA1
Presynaptic nicotinic acetylcholine receptors	1	475.8×	0.006	CHRNA1
Acetylcholine binding and downstream events	1	407.9×	0.006	CHRNA1
Postsynaptic nicotinic acetylcholine receptors	1	407.9×	0.006	CHRNA1
RHO GTPases Activate WASPs and WAVEs	1	158.6×	0.014	WIPF1
FCGR3A-mediated phagocytosis	1	93.6×	0.018	WIPF1
Regulation of actin dynamics for phagocytic cup formation	1	92.1×	0.018	WIPF1
Neurotransmitter receptors and postsynaptic signal transmission	1	50.1×	0.029	CHRNA1
Transmission across Chemical Synapses	1	38.1×	0.032	CHRNA1
CDC42 GTPase cycle	1	36.1×	0.032	WIPF1
RAC1 GTPase cycle	1	30.5×	0.035	WIPF1
Neuronal System	1	22.1×	0.045	CHRNA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to other organism	1	2808.7×	0.005	WIPF1
skeletal muscle tissue growth	1	1404.3×	0.005	CHRNA1
musculoskeletal movement	1	1404.3×	0.005	CHRNA1
synaptic transmission, cholinergic	1	401.2×	0.005	CHRNA1
actin filament-based movement	1	401.2×	0.005	WIPF1
actin polymerization or depolymerization	1	383.0×	0.005	WIPF1
muscle cell cellular homeostasis	1	324.1×	0.005	CHRNA1
acetylcholine receptor signaling pathway	1	312.1×	0.005	CHRNA1
neuromuscular synaptic transmission	1	300.9×	0.005	CHRNA1
neuromuscular junction development	1	263.3×	0.005	CHRNA1
neuromuscular process	1	263.3×	0.005	CHRNA1
skeletal muscle contraction	1	255.3×	0.005	CHRNA1
membrane depolarization	1	255.3×	0.005	CHRNA1
neuronal action potential	1	240.7×	0.005	CHRNA1
neuron cellular homeostasis	1	227.7×	0.005	CHRNA1
presynaptic modulation of chemical synaptic transmission	1	227.7×	0.005	CHRNA1
response to nicotine	1	210.7×	0.006	CHRNA1
regulation of membrane potential	1	115.4×	0.010	CHRNA1
monoatomic ion transmembrane transport	1	104.0×	0.010	CHRNA1
protein-containing complex assembly	1	56.9×	0.017	WIPF1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
CHRNA1	VARENICLINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CHRNA1	12	4
WIPF1	0	0
WIPF1-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARENICLINE	4	CHRNA1
NICOTINE	4	CHRNA1
TROPISETRON	4	CHRNA1
BUPROPION	4	CHRNA1
MECAMYLAMINE	4	CHRNA1
DEXMECAMYLAMINE	3	CHRNA1
CYTISINICLINE	3	CHRNA1
RADAFAXINE	2	CHRNA1
GTS-21	2	CHRNA1
ALTINICLINE	2	CHRNA1
MOLIBRESIB	2	CHRNA1
TC-2216	1	CHRNA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CHRNA1	157	Binding:107, Functional:47, ADMET:2, Toxicity:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CHRNA1	157

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

12 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)
VARENICLINE	4	CHRNA1
NICOTINE	4	CHRNA1
TROPISETRON	4	CHRNA1
BUPROPION	4	CHRNA1
MECAMYLAMINE	4	CHRNA1
DEXMECAMYLAMINE	3	CHRNA1
CYTISINICLINE	3	CHRNA1
RADAFAXINE	2	CHRNA1
GTS-21	2	CHRNA1
ALTINICLINE	2	CHRNA1
MOLIBRESIB	2	CHRNA1
TC-2216	1	CHRNA1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CHRNA1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	WIPF1, WIPF1-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
WIPF1	0	—
WIPF1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.