DOCK4

Chr 7

dedicator of cytokinesis 4

NCBI Gene: 9732ENSG00000128512UniProt: Q8N1I0

This gene is a member of the dedicator of cytokinesis (DOCK) family and encodes a protein with a DHR-1 (CZH-1) domain, a DHR-2 (CZH-2) domain and an SH3 domain. This membrane-associated, cytoplasmic protein functions as a guanine nucleotide exchange factor and is involved in regulation of adherens junctions between cells. Mutations in this gene have been associated with ovarian, prostate, glioma, and colorectal cancers. Alternatively spliced variants which encode different protein isoforms have been described, but only one has been fully characterized. [provided by RefSeq, Jul 2008]

365
ClinVar variants
26
Pathogenic / LP
0.83
pLI score
0
Active trials
Clinical Summary— DOCK4
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.83) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
26 Pathogenic / Likely Pathogenic· 288 VUS of 365 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.30LOEUF
pLI 0.826
Z-score 7.83
OE 0.22 (0.16–0.30)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
2.52Z-score
OE missense 0.78 (0.74–0.83)
826 obs / 1056.1 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.22 (0.16–0.30)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.78 (0.74–0.83)
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.0.96
0≤1.21.6
LoF obs/exp: 25 / 115.9Missense obs/exp: 826 / 1056.1Syn Z: 0.65

ClinVar Variant Classifications

365 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic6
VUS288
Likely Benign35
Benign15
Conflicting1
20
Pathogenic
6
Likely Pathogenic
288
VUS
35
Likely Benign
15
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
20
0
20
Likely Pathogenic
0
3
3
0
6
VUS
3
249
36
0
288
Likely Benign
0
13
8
14
35
Benign
0
5
4
6
15
Conflicting
—1
Total32707120365

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

View in ClinVar →

Protein Context — Lollipop Plot

DOCK4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

DOCK4-related neurodevelopmental disorder

limited
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗
frameshift variantstop gainedmissense variant

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly.
Herbst C et al.·Hum Genet
2024
Genetic variations in DOCK4 contribute to schizophrenia susceptibility in a Chinese cohort: A genetic neuroimaging study.
Xu X et al.·Behav Brain Res
2023Cohort
Construction of a novel radioresistance-related signature for prediction of prognosis, immune microenvironment and anti-tumour drug sensitivity in non-small cell lung cancer.
Chen Y et al.·Ann Med
2025
Identification of DOCK4 and its splicing variant as PIP3 binding proteins.
Kanai A et al.·IUBMB Life
2008
Aberrant epigenetic and genetic marks are seen in myelodysplastic leukocytes and reveal Dock4 as a candidate pathogenic gene on chromosome 7q.
Zhou L et al.·J Biol Chem
2011
High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility.
Maestrini E et al.·Mol Psychiatry
2010
Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes.
Sundaravel S et al.·Proc Natl Acad Sci U S A
2015
A potential therapeutic molecule target: lncRNA AK023507 inhibits the metastasis of breast cancer by regulating the WNT/DOCK4/β-catenin axis.
Diao B et al.·Breast Cancer Res Treat
2025
Identification and validation of DOCK4 as a potential biomarker for risk of bone metastasis development in patients with early breast cancer.
Westbrook JA et al.·J Pathol
2019Cohort
Up-regulated cytotrophoblast DOCK4 contributes to over-invasion in placenta accreta spectrum.
McNally L et al.·Proc Natl Acad Sci U S A
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
TMOD2 and DOCK4 as Novel Gut Microbiota-Associated Biomarkers for Colorectal Adenoma: Integrated Transcriptomic Analysis and Therapeutic Target Identification.
Liu C et al.·Mediators Inflamm
2025🔓 Open Access
Could the Polymorphisms of DOCK4 (rs147636134), SYNGAP1 (rs199759879), and FOXP1 (rs767001715) be the Primary Risk Factors for Bipolar Disorder and Autism Spectrum Disorder?
Çiftçi E et al.·Dev Neurobiol
2025🔓 Open Access
Histone lactylation regulates DOCK4 to control heat nociception and supports Dynein-mediated Nav1.7 trafficking.
Xie MX et al.·Nat Commun
2025🔓 Open Access
LncRNA OIP5-AS1 suppresses lung adenocarcinoma progression and modulates macrophage polarization through the miR-429/DOCK4 regulatory axis.
Liu Y et al.·Front Pharmacol
2025🔓 Open Access
THEMIS2 contributes to ovarian cancer metastasis via DOCK4-mediated activation of Rap1 signaling.
Zhou K et al.·Cell Oncol (Dordr)
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools