# NM_001367561.1(DOCK7):c.783del (p.Phe261fs)

https://sugi.bio/variant/dock7-p-phe261fs

## Summary

**DOCK7 p.Phe261fs (c.783del)** is classified **Pathogenic** in DOCK7 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-01-24). No gnomAD frequency available for this variant; Associated with developmental and epileptic encephalopathy, 23.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1557855477 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DOCK7 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to developmental and epileptic encephalopathy, 23.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017687/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DOCK7](https://sugi.bio/atlas/gene/DOCK7/) |
| Protein change (HGVS p.) | p.Phe261fs |
| Coding change (HGVS c.) | c.783del |
| MANE Select transcript | [NM_001367561](https://www.ncbi.nlm.nih.gov/nuccore/NM_001367561) |
| dbSNP | [rs1557855477](https://www.ncbi.nlm.nih.gov/snp/rs1557855477/) |
| Variant type | Deletion |
| Location | chr1:62647726-62647726 (GRCh38) |
| ClinVar | [VCV581758](https://www.ncbi.nlm.nih.gov/clinvar/variation/581758/) |

**All HGVS expressions:** `NC_000001.10:g.63113400del`, `NC_000001.11:g.62647729del`, `NG_033073.2:g.45643del`, `NM_001271999.1:c.783delT`, `NM_001271999.2:c.783del`, `NM_001272000.2:c.783del`, `NM_001272001.2:c.783del`, `NM_001272002.2:c.783del`, `NM_001330614.2:c.783del`, `NM_001367561.1:c.783del`, `NM_033407.4:c.783del`

## 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 7.686, GERP 2.65, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.551, pLI 8.7006e-08. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 50**, 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.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**DOCK7** population constraint: LOEUF 0.551, pLI 8.7006e-08, missense-Z 3.8839; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **genetic developmental and epileptic encephalopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 74.60, 27% of residues very-high.

**2 experimental structure(s)** (PDB): [6AJ4](https://www.rcsb.org/structure/6AJ4), [6AJL](https://www.rcsb.org/structure/6AJL) — incl. mutant structure 6AJL.

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

*Describes the biological roles of DOCK7 (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:** DOCK7's established molecular role includes GTPase activator activity.


### Pathways affected {#pathways}

DOCK7 participates in **4 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 |
| [MET activates RAP1 and RAC1](https://reactome.org/content/detail/R-HSA-8875555) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |

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

**Molecular function:** GTPase activator activity, small GTPase binding.

**Biological process:** microtubule cytoskeleton organization, axonogenesis, Rac protein signal transduction, neuron projection development, establishment of neuroblast polarity, positive regulation of vascular associated smooth muscle cell migration.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-01-24.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2020-01-24 |

## Associated conditions {#conditions}

[developmental and epileptic encephalopathy, 23](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-23/).

**Reported phenotype names (ClinVar):** Developmental and epileptic encephalopathy, 23, Epileptic encephalopathy, early infantile, 23.

## Similar variants {#similar}

Related DOCK7 variant pages (same residue, condition, or type): [DOCK7 p.Phe1206fs](/variant/dock7-p-phe1206fs), [DOCK7 p.Met1284del](/variant/dock7-p-met1284del), [DOCK7 c.1283-14del](/variant/dock7-c-1283-minus-14del), [DOCK7 c.1872-9del](/variant/dock7-c-1872-minus-9del), [DOCK7 c.3781+15_3781+56del](/variant/dock7-c-3781-plus-15-3781-plus-56del), [DOCK7 c.3187-31_3274del](/variant/dock7-c-3187-minus-31-3274del), [DOCK7 c.3937-686_4597del](/variant/dock7-c-3937-minus-686-4597del), [DOCK7 p.Arg576fs](/variant/dock7-p-arg576fs).

### 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 581758). 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.*