# NM_004946.3(DOCK2):c.2229_2230dup (p.Phe744fs)

https://sugi.bio/variant/dock2-p-phe744fs

## Summary

**DOCK2 p.Phe744fs (c.2229_2230dup)** is classified **Pathogenic** in DOCK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2015-06-18). No gnomAD frequency available for this variant; Associated with DOCK2 deficiency.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs2113559002 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DOCK2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to DOCK2 deficiency.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | DOCK2 is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012653/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DOCK2](https://sugi.bio/atlas/gene/DOCK2/) |
| Protein change (HGVS p.) | p.Phe744fs |
| Coding change (HGVS c.) | c.2229_2230dup |
| MANE Select transcript | [NM_004946](https://www.ncbi.nlm.nih.gov/nuccore/NM_004946) |
| dbSNP | [rs2113559002](https://www.ncbi.nlm.nih.gov/snp/rs2113559002/) |
| Variant type | Microsatellite |
| Location | chr5:169718749-169718750 (GRCh38) |
| ClinVar | [VCV199262](https://www.ncbi.nlm.nih.gov/clinvar/variation/199262/) |

**All HGVS expressions:** `LRG_1227:g.86505GT[3]`, `LRG_1227t1:c.2229_2230dup`, `NC_000005.10:g.169718751GT[3]`, `NC_000005.9:g.169145755GT[3]`, `NG_051800.1:g.86505GT[3]`, `NM_004946.3:c.2229_2230dup`, `NR_156756.1:n.2279GT[3]`

## 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 11.085, GERP 2.42, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.421, 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 22 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 microsatellite 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}

**DOCK2** population constraint: LOEUF 0.421, pLI 1, missense-Z 4.9199. *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):

- **DOCK2 deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.40, 44% of residues very-high.

**6 experimental structure(s)** (PDB): [2RQR](https://www.rcsb.org/structure/2RQR), [2YIN](https://www.rcsb.org/structure/2YIN), [3A98](https://www.rcsb.org/structure/3A98), [3B13](https://www.rcsb.org/structure/3B13), [6TGB](https://www.rcsb.org/structure/6TGB), [6TGC](https://www.rcsb.org/structure/6TGC) — incl. mutant structure 3B13.

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

*Describes the biological roles of DOCK2 (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:** DOCK2's established molecular role includes guanyl-nucleotide exchange factor activity. In Reactome, DOCK2 is annotated in disease pathway(s) including **Nef and signal transduction**.

**Disease mechanism (Reactome):** DOCK2 loss or alteration is curated in [Nef and signal transduction](https://reactome.org/content/detail/R-HSA-164944).

### Pathways affected {#pathways}

DOCK2 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Nef and signal transduction](https://reactome.org/content/detail/R-HSA-164944) | curated |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | 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 |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | curated |

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

**Molecular function:** guanyl-nucleotide exchange factor activity, T cell receptor binding.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2015-06-18.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2015-06-18 |

## Associated conditions {#conditions}

[DOCK2 deficiency](https://sugi.bio/atlas/disease/dock2-deficiency/).

**Reported phenotype names (ClinVar):** DOCK2 deficiency, Immunodeficiency 40.

## Similar variants {#similar}

Related DOCK2 variant pages (same residue, condition, or type): [DOCK2 p.Arg444fs](/variant/dock2-p-arg444fs), [DOCK2 c.1482+6_1482+8del](/variant/dock2-c-1482-plus-6-1482-plus-8del), [DOCK2 c.3233-9_3233-5del](/variant/dock2-c-3233-minus-9-3233-minus-5del), [DOCK2 c.1056-18CT[2]](/variant/dock2-c-1056-minus-18ct-2), [DOCK2 c.1259-22TC[3]](/variant/dock2-c-1259-minus-22tc-3), [DOCK2 c.2031+4AG[3]](/variant/dock2-c-2031-plus-4ag-3), [DOCK2 c.2133-14_2133-12del](/variant/dock2-c-2133-minus-14-2133-minus-12del), [DOCK2 c.2447+15_2447+17del](/variant/dock2-c-2447-plus-15-2447-plus-17del).

### 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 199262). 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.*