# NM_001290223.2(DOCK1):c.2053dup (p.Glu685fs)

https://sugi.bio/variant/dock1-p-glu685fs

## Summary

**DOCK1 p.Glu685fs (c.2053dup)** is classified **Likely pathogenic** in DOCK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-05-17). Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs767858333 · 1 submitter · 1 linked condition · very rare (popmax 0.00333%, amr)

## For patients & families {#patients}

This is a change in the DOCK1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [DOCK1](https://sugi.bio/atlas/gene/DOCK1/) |
| Protein change (HGVS p.) | p.Glu685fs |
| Coding change (HGVS c.) | c.2053dup |
| MANE Select transcript | [NM_001290223](https://www.ncbi.nlm.nih.gov/nuccore/NM_001290223) |
| dbSNP | [rs767858333](https://www.ncbi.nlm.nih.gov/snp/rs767858333/) |
| Variant type | Duplication |
| Location | chr10:127042665-127042666 (GRCh38) |
| ClinVar | [VCV521686](https://www.ncbi.nlm.nih.gov/clinvar/variation/521686/) |

**All HGVS expressions:** `NC_000010.10:g.128840931dup`, `NC_000010.11:g.127042667dup`, `NG_033919.2:g.142214dup`, `NM_001290223.2:c.2053dup`, `NM_001377543.1:c.1990dup`, `NM_001377544.1:c.2026dup`, `NM_001377546.1:c.2053dup`, `NM_001377547.1:c.1927dup`, `NM_001377548.1:c.1906dup`, `NM_001377550.1:c.1891dup`, `NM_001377553.1:c.1990dup`, `NM_001377554.1:c.1837dup`, `NM_001377556.1:c.1990dup`, `NM_001377558.1:c.1837dup`, `NM_001377560.1:c.1198dup`, `NM_001377561.1:c.2053dup`, `NM_001380.5:c.1990dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.737, GERP 2.69, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.637, pLI 1.9567e-18. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 20 of 52**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00333%** (amr) · FAF95 0.000553% · FAF99 0.000207% · 2/60,022 in the highest group · 9/1,461,862 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00333% | 30,011 |
| African / African-American | 0.00133% | 75,042 |
| European (non-Finnish) | 0.000508% | 196,669 |

*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}

**DOCK1** population constraint: LOEUF 0.637, pLI 1.9567e-18, missense-Z 3.3656. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.63, 41% of residues very-high.

**1 experimental structure(s)** (PDB): [3L4C](https://www.rcsb.org/structure/3L4C).

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

*Describes the biological roles of DOCK1 (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.*

**How this variant is thought to act:** DOCK1 participates in disease-associated pathways. In Reactome, DOCK1 is annotated in disease pathway(s) including **FCGR3A-mediated phagocytosis**.

**Disease mechanism (Reactome):** DOCK1 loss or alteration is curated in [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422).

### Pathways affected {#pathways}

DOCK1 participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | curated |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases](https://reactome.org/content/detail/R-HSA-8849471) | 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 |
| [Regulation of actin dynamics for phagocytic cup formation](https://reactome.org/content/detail/R-HSA-2029482) | curated |
| [SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)](https://reactome.org/content/detail/R-HSA-9958810) | curated |
| [VEGFA-VEGFR2 Pathway](https://reactome.org/content/detail/R-HSA-4420097) | curated |
| [DCC mediated attractive signaling](https://reactome.org/content/detail/R-HSA-418885) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** positive regulation of epithelial cell migration, regulation of postsynapse assembly, positive regulation of substrate adhesion-dependent cell spreading.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2017-05-17.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2017-05-17 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related DOCK1 variant pages (same residue, condition, or type): [DOCK1 p.Lys148del](/variant/dock1-p-lys148del).

### 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 521686). 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.*