DOCK3

Chr 3AR

dedicator of cytokinesis 3

Also known as: MOCA, NEDIDHA, PBP

NCBI Gene: 1795 ENSG00000088538 UniProt: Q8IZD9 OMIM: 603123

DOCK3 encodes a guanine nucleotide exchange factor that activates Rac1 and induces axonal outgrowth in the central nervous system through stimulation of the WAVE complex. Biallelic mutations cause autosomal recessive neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia. The gene is highly constrained against loss-of-function variants (pLI >0.99, LOEUF 0.158), indicating that functional copies are critical for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is specifically expressed in the central nervous system (CNS). It encodes a member of the DOCK (dedicator of cytokinesis) family of guanine nucleotide exchange factors (GEFs). This protein, dedicator of cytokinesis 3 (DOCK3), is also known as modifier of cell adhesion (MOCA) and presenilin-binding protein (PBP). The DOCK3 and DOCK1, -2 and -4 share several conserved amino acids in their DHR-2 (DOCK homology region 2) domains that are required for GEF activity, and bind directly to WAVE proteins [Wiskott-Aldrich syndrome protein (WASP) family Verprolin-homologous proteins] via their DHR-1 domains. The DOCK3 induces axonal outgrowth in CNS by stimulating membrane recruitment of the WAVE complex and activating the small G protein Rac1. This gene is associated with an attention deficit hyperactivity disorder-like phenotype by a complex chromosomal rearrangement. [provided by RefSeq, Aug 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.161 OMIM phenotype

Clinical Summary— DOCK3

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

14 unique Pathogenic / Likely Pathogenic· 233 VUS of 341 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.16LOEUF

pLI 1.000

Z-score 9.00

OE 0.10 (0.06–0.16)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.94Z-score

OE missense 0.67 (0.63–0.71)

766 obs / 1139.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.10 (0.06–0.16)

0≤0.351.4

Missense OE?0.67 (0.63–0.71)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 11 / 115.3Missense obs/exp: 766 / 1139.9Syn Z: -0.00

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateDOCK3-related neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxiaLOFAR

This gene — mechanism propensity

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

0.3991th %ile

GOF

0.5171th %ile

LOF

0.66top 25%

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

341 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic6

VUS233

Likely Benign44

Benign4

Conflicting3

Pathogenic

Likely Pathogenic

233

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	7	0	1	0	8
Likely Pathogenic	6	0	0	0	6
VUS	6	224	3	0	233
Likely Benign	0	8	3	33	44
Benign	0	1	2	1	4
Conflicting	—				3
Total	19	233	9	34	298

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap DOCK3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →