DOCK8

Chr 9AR

dedicator of cytokinesis 8

Also known as: HEL-205, HIES2, MRD2, ZIR8

NCBI Gene: 81704ENSG00000107099UniProt: Q8NF50

This gene encodes a member of the DOCK180 family of guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with Rho GTPases and are components of intracellular signaling networks. Mutations in this gene result in the autosomal recessive form of the hyper-IgE syndrome. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Jun 2010]

Primary Disease Associations & Inheritance

Hyper-IgE syndrome 2, autosomal recessive, with recurrent infectionsMIM #243700
AR
UniProtIntellectual developmental disorder, autosomal dominant 2
3644
ClinVar variants
10
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— DOCK8
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
10 Pathogenic / Likely Pathogenic· 50 VUS of 3644 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.48LOEUF
pLI 0.000
Z-score 6.08
OE 0.36 (0.28–0.48)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-2.54Z-score
OE missense 1.21 (1.16–1.27)
1380 obs / 1138.4 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.36 (0.28–0.48)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.21 (1.16–1.27)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.32
0≤1.21.6
LoF obs/exp: 39 / 106.9Missense obs/exp: 1380 / 1138.4Syn Z: -5.29

ClinVar Variant Classifications

3644 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3
Likely Pathogenic7
VUS50
Likely Benign140
3
Pathogenic
7
Likely Pathogenic
50
VUS
140
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
2
0
3
Likely Pathogenic
3
0
4
0
7
VUS
0
43
7
0
50
Likely Benign
0
1
70
69
140
Benign
0
0
0
0
0
Total4448369200

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

DOCK8 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

DOCK8-related hyper-IgE syndrome with recurrent infections

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Hyper-IgE syndrome 2, autosomal recessive, with recurrent infections

MIM #243700

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Hyper IgE syndromes: clinical and molecular characteristics.
Al-Shaikhly T et al.·Immunol Cell Biol
2019Review
Hyper IgE syndromes: A clinical approach.
Gharehzadehshirazi A et al.·Clin Immunol
2022Review
De novo genic mutations among a Chinese autism spectrum disorder cohort.
Wang T et al.·Nat Commun
2016Cohort
Hyper IgE Syndromes.
Gracci S et al.·Curr Pediatr Rev
2024
Type 2 immunity in the skin and lungs.
Akdis CA et al.·Allergy
2020Review
DOCK8 deficiency.
Gennery AR et al.·Curr Opin Allergy Clin Immunol
2025Review
DOCK8 deficiency.
Su HC et al.·Ann N Y Acad Sci
2011Review
DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity.
Boussard C et al.·Blood
2023Case report
Hyper IgE Syndrome: Bridging the Gap Between Immunodeficiency, Atopy, and Allergic Diseases.
Sutanto H et al.·Curr Allergy Asthma Rep
2025Review
DOCK8 deficiency: Insights into pathophysiology, clinical features and management.
Biggs CM et al.·Clin Immunol
2017Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Primary ImmunodeficiencyDOCK8Virus Susceptibility

Establishing Fibroblast-Derived Cell Lines From Skin Biopsies of Patients With Immunodeficiency or Immunodysregulation Disorders

ENROLLING BY INVITATION
NCT00895271National Institute of Allergy and Infectious Diseases (NIAID)Started 2009-06-10
LAD-1DOCK8GATA2 Deficancy

Apheresis of Patients With Immunodeficiency

RECRUITING
NCT01212055National Cancer Institute (NCI)Started 2010-11-08

External Resources

Links to major genomics databases and tools