# NM_020812.4(DOCK6):c.82dup (p.Glu28fs)

https://sugi.bio/variant/dock6-p-glu28fs

## Summary

**DOCK6 p.Glu28fs (c.82dup)** is classified **Likely pathogenic** in DOCK6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-25). Very rare (popmax 0.000179%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.000179%, nfe)

## For patients & families {#patients}

This is a change in the DOCK6 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 | [DOCK6](https://sugi.bio/atlas/gene/DOCK6/) |
| Protein change (HGVS p.) | p.Glu28fs |
| Coding change (HGVS c.) | c.82dup |
| MANE Select transcript | [NM_020812](https://www.ncbi.nlm.nih.gov/nuccore/NM_020812) |
| Variant type | Duplication |
| Location | chr19:11253688-11253689 (GRCh38) |
| ClinVar | [VCV3504522](https://www.ncbi.nlm.nih.gov/clinvar/variation/3504522/) |

**All HGVS expressions:** `NC_000019.10:g.11253691dup`, `NC_000019.9:g.11364367dup`, `NG_031953.1:g.13804dup`, `NG_140417.1:g.75dup`, `NG_147918.1:g.1044dup`, `NM_001367830.1:c.82dup`, `NM_020812.4:c.82dup`

## 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 7.651, GERP 2.43, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.87, pLI 1.38e-40. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 48**, 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 **0.000179%** (nfe) · FAF95 3e-05% · FAF99 1.1e-05% · 2/1,118,846 in the highest group · 2/1,319,302 alleles overall — very rare (popmax 0.000179%, nfe).

*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}

**DOCK6** population constraint: LOEUF 0.87, pLI 1.38e-40, missense-Z 0.83921. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Adams-Oliver syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **28** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 77.78, 30% of residues very-high.

**7 experimental structure(s)** (PDB): [9VM2](https://www.rcsb.org/structure/9VM2), [9VM3](https://www.rcsb.org/structure/9VM3), [9VM4](https://www.rcsb.org/structure/9VM4), [9VM5](https://www.rcsb.org/structure/9VM5), [9VM6](https://www.rcsb.org/structure/9VM6), [9VM7](https://www.rcsb.org/structure/9VM7).

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

*Describes the biological roles of DOCK6 (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}

DOCK6 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [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 |

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-25.

**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 | 2024-06-25 |

## 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 DOCK6 variant pages (same residue, condition, or type): [DOCK6 p.Glu28Asp](/variant/dock6-p-glu28asp), [DOCK6 c.5939+2T>C](/variant/dock6-c-5939-plus-2t-c), [DOCK6 p.Glu1494Ter](/variant/dock6-p-glu1494ter), [DOCK6 p.Thr455fs](/variant/dock6-p-thr455fs), [DOCK6 p.Ala1153Thr](/variant/dock6-p-ala1153thr), [DOCK6 p.Ala1207Val](/variant/dock6-p-ala1207val), [DOCK6 p.Ala1241Thr](/variant/dock6-p-ala1241thr), [DOCK6 p.Ala1319Val](/variant/dock6-p-ala1319val).

### 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 3504522). 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.*