# NM_001367561.1(DOCK7):c.3326C>T (p.Pro1109Leu)

https://sugi.bio/variant/dock7-p-pro1109leu

## Summary

**DOCK7 p.Pro1109Leu (c.3326C>T)** is classified **Uncertain significance** in DOCK7 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-16). AlphaMissense: likely benign (0.1424); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs537709953 · 4 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the DOCK7 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 submitters, 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 | [DOCK7](https://sugi.bio/atlas/gene/DOCK7/) |
| Protein change (HGVS p.) | p.Pro1109Leu |
| Coding change (HGVS c.) | c.3326C>T |
| MANE Select transcript | [NM_001367561](https://www.ncbi.nlm.nih.gov/nuccore/NM_001367561) |
| dbSNP | [rs537709953](https://www.ncbi.nlm.nih.gov/snp/rs537709953/) |
| Variant type | single nucleotide variant |
| Location | chr1:62538036-62538036 (GRCh38) |
| ClinVar | [VCV640279](https://www.ncbi.nlm.nih.gov/clinvar/variation/640279/) |

**All HGVS expressions:** `NC_000001.10:g.63003707G>A`, `NC_000001.11:g.62538036G>A`, `NG_033073.2:g.155333C>T`, `NM_001271999.2:c.3326C>T`, `NM_001272000.2:c.3233C>T`, `NM_001272001.2:c.3233C>T`, `NM_001330614.2:c.3326C>T`, `NM_001367561.1:c.3326C>T`, `NM_033407.2:c.3233C>T`, `NM_033407.4:c.3233C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1424)
- REVEL 0.149 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.164 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 11.833, GERP 2.16, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.5**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.85** across the covering region of the MANE Select transcript (62,513,597–62,688,264), spanning 174,667 bp. Chi-square p 3.6e-10. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.94 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 0.000803% · FAF99 0.00065% · 1/44,842 in the highest group · 18/1,613,604 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,842 |
| European (non-Finnish) | 0.00136% | 73,737 |
| South Asian | 0.0011% | 91,004 |

*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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-16.

**Submitter consensus:** unanimous (4/4 Uncertain significance).

**Submission history:** 4 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome-Nilou Lab | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-04-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-23 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-12-14 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-16 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Developmental and epileptic encephalopathy, 23, not provided, Epileptic encephalopathy, early infantile, 23, none provided.

## Similar variants {#similar}

Related DOCK7 variant pages (same residue, condition, or type): [DOCK7 p.Pro1109=](/variant/dock7-p-pro1109), [DOCK7 c.4924-1G>A](/variant/dock7-c-4924-minus-1g-a), [DOCK7 p.Arg1380Ter](/variant/dock7-p-arg1380ter), [DOCK7 p.Arg1415Ter](/variant/dock7-p-arg1415ter), [DOCK7 p.Arg429Ter](/variant/dock7-p-arg429ter), [DOCK7 p.Arg445Ter](/variant/dock7-p-arg445ter), [DOCK7 c.3781+4C>G](/variant/dock7-c-3781-plus-4c-g), [DOCK7 c.38+6T>C](/variant/dock7-c-38-plus-6t-c).

### 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 640279). 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.*