DOCK6

Chr 19AR

dedicator of cytokinesis 6

Also known as: AOS2, ZIR1

NCBI Gene: 57572 ENSG00000130158 UniProt: Q96HP0 OMIM: 614194

The protein acts as a guanine nucleotide exchange factor that activates CDC42 and RAC1 small GTPases, regulating actin cytoskeletal reorganization and neurite outgrowth. Biallelic mutations cause Adams-Oliver syndrome 2, a congenital disorder characterized by scalp defects and limb malformations, inherited in an autosomal recessive pattern. The gene shows moderate constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the dedicator of cytokinesis (DOCK) family of atypical guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with small GTPases and are components of intracellular signaling networks. The encoded protein is a group C DOCK protein and plays a role in actin cytoskeletal reorganization by activating the Rho GTPases Cdc42 and Rac1. Mutations in this gene are associated with Adams-Oliver syndrome 2. [provided by RefSeq, Dec 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.721 OMIM phenotype

Clinical Summary— DOCK6

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Gene-Disease Validity (ClinGen)

Adams-Oliver syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

107 unique Pathogenic / Likely Pathogenic· 719 VUS of 1760 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.72LOEUF

pLI 0.000

Z-score 3.96

OE 0.58 (0.47–0.72)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.43Z-score

OE missense 0.89 (0.85–0.93)

1160 obs / 1305.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.58 (0.47–0.72)

0≤0.351.4

Missense OE?0.89 (0.85–0.93)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 59 / 102.2Missense obs/exp: 1160 / 1305.9Syn Z: 0.72

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongDOCK6-related Adams-Oliver syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6064th %ile

GOF

0.6443th %ile

LOF

0.3550th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

1760 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic56

Likely Pathogenic51

VUS719

Likely Benign746

Benign110

Conflicting31

Pathogenic

Likely Pathogenic

719

VUS

746

Likely Benign

110

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	50	1	5	0	56
Likely Pathogenic	49	0	2	0	51
VUS	5	672	34	8	719
Likely Benign	2	29	322	393	746
Benign	1	7	77	25	110
Conflicting	—				31
Total	107	709	440	426	1,713

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap DOCK6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →