DOCK6

Chr 19

dedicator of cytokinesis 6

Also known as: AOS2, ZIR1

NCBI Gene: 57572 ENSG00000130158 UniProt: Q96HP0

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.

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]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtAdams-Oliver syndrome 2

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Adams-Oliver syndrome · AR · ClinGen 2022

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.72

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in DOCK6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 17

2,931 rare PASS variants

Rare truncating (LoF)

1 in 220

441 rare PASS variants

Rare synonymous (reference)

1 in 28

1,275 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DOCK6. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 23	1 in 210
South Asian	~43k	1 in 15	1 in 180
Remaining (unassigned)	~30k	1 in 15	1 in 310
European (Finnish)	~27k	1 in 48	1 in 700
Admixed American	~22k	1 in 14	1 in 170
African / African American	~21k	1 in 18	1 in 200
East Asian	~20k	1 in 16	1 in 250
Ashkenazi Jewish	~13k	1 in 64	1 in 210
Middle Eastern	~2,884	1 in 16	1 in 250

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.