DOCK2 deficiency

Summary

DOCK2 deficiency (MONDO:0014637) is a disease caused by DOCK2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DOCK2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 1,136

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	DOCK2 deficiency
Mondo ID	MONDO:0014637
OMIM	616433
Orphanet	447737
DOID	DOID:0111951
UMLS	C4225328
MedGen	901370
GARD	0012653
Is cancer (heuristic)	no

Also known as: IMD40 · immunodeficiency 40 · immunodeficiency type 40

Data availability: 1,136 ClinVar variants · 5 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 › DOCK2 deficiency

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, Wiskott-Aldrich syndrome 2, cryptosporidiosis-chronic cholangitis-liver disease syndrome, idiopathic CD4 lymphocytopenia, immunodeficiency 23, 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

600 retrieved; paginated sample, class counts are floors:

320 likely benign, 233 uncertain significance, 20 benign, 12 pathogenic, 6 likely pathogenic, 5 conflicting classifications of pathogenicity, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2425244	NC_000005.9:g.(?167849013)(169661202_?)del	C5orf58	Pathogenic	criteria provided, single submitter
1065180	NM_004946.3(DOCK2):c.471-2A>G	DOCK2	Pathogenic	criteria provided, single submitter
1070423	NM_004946.3(DOCK2):c.1348_1349del (p.Met450fs)	DOCK2	Pathogenic	criteria provided, single submitter
1070656	NM_004946.3(DOCK2):c.4786C>T (p.Arg1596Ter)	DOCK2	Pathogenic	criteria provided, single submitter
1071464	NM_004946.3(DOCK2):c.4858C>T (p.Arg1620Ter)	DOCK2	Pathogenic	criteria provided, single submitter
1075139	NM_004946.3(DOCK2):c.316dup (p.Tyr106fs)	DOCK2	Pathogenic	criteria provided, single submitter
1454578	NM_004946.3(DOCK2):c.149dup (p.His52fs)	DOCK2	Pathogenic	criteria provided, single submitter
199258	NM_004946.3(DOCK2):c.3724_3725dup (p.Leu1244fs)	DOCK2	Pathogenic	no assertion criteria provided
199259	NM_004946.3(DOCK2):c.3970C>T (p.Gln1324Ter)	DOCK2	Pathogenic	no assertion criteria provided
199261	NM_004946.3(DOCK2):c.2253G>T (p.Arg751Ser)	DOCK2	Pathogenic	no assertion criteria provided
199262	NM_004946.3(DOCK2):c.2229_2230dup (p.Phe744fs)	DOCK2	Pathogenic	no assertion criteria provided
2154774	NM_004946.3(DOCK2):c.1847del (p.Gly616fs)	DOCK2	Pathogenic	criteria provided, single submitter
1028824	NM_004946.3(DOCK2):c.4729-2A>G	DOCK2	Likely pathogenic	criteria provided, single submitter
1481167	NM_004946.3(DOCK2):c.3756+2T>C	DOCK2	Likely pathogenic	criteria provided, single submitter
199260	NM_004946.3(DOCK2):c.3310C>T (p.Arg1104Trp)	DOCK2	Likely pathogenic	criteria provided, single submitter
2008486	NM_004946.3(DOCK2):c.4072-1G>C	DOCK2	Likely pathogenic	criteria provided, single submitter
2098039	NM_004946.3(DOCK2):c.1055+1G>A	DOCK2	Likely pathogenic	criteria provided, single submitter
2584986	NM_004946.3(DOCK2):c.1055+1G>T	DOCK2	Likely pathogenic	criteria provided, single submitter
1028312	NM_004946.3(DOCK2):c.1384-4T>C	DOCK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1034136	NM_004946.3(DOCK2):c.3073-8A>G	DOCK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1119106	NM_004946.3(DOCK2):c.3174-8C>T	DOCK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1499273	NM_004946.3(DOCK2):c.2553A>G (p.Gln851=)	DOCK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1673249	NM_004946.3(DOCK2):c.1546T>C (p.Ser516Pro)	DOCK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1000384	NM_004946.3(DOCK2):c.5402A>G (p.Lys1801Arg)	DOCK2	Uncertain significance	criteria provided, single submitter
1000648	NM_004946.3(DOCK2):c.4906A>G (p.Met1636Val)	DOCK2	Uncertain significance	criteria provided, single submitter
1002734	NM_004946.3(DOCK2):c.5305G>A (p.Ala1769Thr)	DOCK2	Uncertain significance	criteria provided, single submitter
1007320	NM_004946.3(DOCK2):c.1075T>C (p.Phe359Leu)	DOCK2	Uncertain significance	criteria provided, single submitter
1009043	NM_004946.3(DOCK2):c.5377G>A (p.Gly1793Ser)	DOCK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1009243	NM_004946.3(DOCK2):c.1384-3C>T	DOCK2	Uncertain significance	criteria provided, single submitter
1009395	NM_004946.3(DOCK2):c.215A>T (p.Glu72Val)	DOCK2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
DOCK2	Definitive	Autosomal recessive	DOCK2 deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DOCK2	Orphanet:447737	Combined immunodeficiency due to DOCK2 deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DOCK2	HGNC:2988	ENSG00000134516	Q92608	Dedicator of cytokinesis protein 2	gencc,clinvar
C5orf58	HGNC:37272	ENSG00000234511	C9J3I9	Putative uncharacterized protein C5orf58	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DOCK2	Dedicator of cytokinesis protein 2	Involved in cytoskeletal rearrangements required for lymphocyte migration in response of chemokines.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DOCK2	Scaffold/PPI	no		SH3_domain, ARM-type_fold, DOCK
C5orf58	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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow cell	1
monocyte	1
mononuclear cell	1
left testis	1
right testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DOCK2	216	broad	marker	bone marrow cell, monocyte, mononuclear cell
C5orf58	155	tissue_specific	marker	right testis, left testis, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DOCK2	2,278
C5orf58	97

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DOCK2	Q92608	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C5orf58	C9J3I9	76.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 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
Nef and signal transduction	1	1268.9×	0.006	DOCK2
RHOG GTPase cycle	1	148.3×	0.018	DOCK2
RAC2 GTPase cycle	1	126.9×	0.018	DOCK2
RHOA GTPase cycle	1	74.6×	0.019	DOCK2
Factors involved in megakaryocyte development and platelet production	1	66.4×	0.019	DOCK2
RAC1 GTPase cycle	1	61.1×	0.019	DOCK2
Neutrophil degranulation	1	23.1×	0.043	DOCK2

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
membrane raft polarization	1	5617.3×	9e-04	DOCK2
myeloid dendritic cell activation involved in immune response	1	5617.3×	9e-04	DOCK2
alpha-beta T cell proliferation	1	5617.3×	9e-04	DOCK2
establishment of T cell polarity	1	1872.4×	0.001	DOCK2
macropinocytosis	1	1872.4×	0.001	DOCK2
positive thymic T cell selection	1	1404.3×	0.001	DOCK2
negative thymic T cell selection	1	1404.3×	0.001	DOCK2
immunological synapse formation	1	1296.3×	0.001	DOCK2
myoblast fusion	1	601.9×	0.003	DOCK2
positive regulation of phagocytosis	1	318.0×	0.005	DOCK2
small GTPase-mediated signal transduction	1	183.2×	0.007	DOCK2
regulation of small GTPase mediated signal transduction	1	144.0×	0.008	DOCK2
chemotaxis	1	135.9×	0.008	DOCK2
actin cytoskeleton organization	1	79.1×	0.014	DOCK2
cell migration	1	61.5×	0.016	DOCK2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DOCK2	1	2
C5orf58	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	DOCK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
DOCK2	11	Binding:11

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

1 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)
MOLIBRESIB	2	DOCK2

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	1	DOCK2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	C5orf58

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)
C5orf58	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.