# NM_004947.5(DOCK3):c.1805_1806del (p.Lys602fs)

https://sugi.bio/variant/dock3-p-lys602fs

## Summary

**DOCK3 p.Lys602fs (c.1805_1806del)** is classified **Pathogenic** in DOCK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09).

**At a glance:** Pathogenic · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the DOCK3 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DOCK3](https://sugi.bio/atlas/gene/DOCK3/) |
| Protein change (HGVS p.) | p.Lys602fs |
| Coding change (HGVS c.) | c.1805_1806del |
| MANE Select transcript | [NM_004947](https://www.ncbi.nlm.nih.gov/nuccore/NM_004947) |
| Variant type | Deletion |
| Location | chr3:51228817-51228818 (GRCh38) |
| ClinVar | [VCV4529747](https://www.ncbi.nlm.nih.gov/clinvar/variation/4529747/) |

**All HGVS expressions:** `NC_000003.11:g.51266249_51266250del`, `NC_000003.12:g.51228818_51228819del`, `NG_028012.2:g.558578_558579del`, `NM_004947.5:c.1805_1806del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.592, GERP -3.69, phastCons 0.998 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.298, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 18 of 53**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**DOCK3** population constraint: LOEUF 0.298, pLI 1, missense-Z 4.3974. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **602** lies in a UniProt-annotated variant site (in nedidha).

AlphaFold model confidence (whole protein): pLDDT 75.52, 36% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of DOCK3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

DOCK3 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | curated |
| [NTRK2 activates RAC1](https://reactome.org/content/detail/R-HSA-9032759) | electronic |

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-09.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-09 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related DOCK3 variant pages (same residue, condition, or type): [DOCK3 p.Pro1406fs](/variant/dock3-p-pro1406fs), [DOCK3 p.Arg72fs](/variant/dock3-p-arg72fs), [DOCK3 p.Leu1411fs](/variant/dock3-p-leu1411fs), [DOCK3 p.Lys589fs](/variant/dock3-p-lys589fs), [DOCK3 c.5407_5412+16del](/variant/dock3-c-5407-5412-plus-16del), [DOCK3 p.Arg1981fs](/variant/dock3-p-arg1981fs), [DOCK3 p.Gly11_Val12insTer](/variant/dock3-p-gly11-val12inster), [DOCK3 p.Trp1081fs](/variant/dock3-p-trp1081fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4529747). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*