# NM_004946.3(DOCK2):c.1793A>T (p.Asp598Val)

https://sugi.bio/variant/dock2-p-asp598val

## Summary

**DOCK2 p.Asp598Val (c.1793A>T)** is classified **Uncertain significance** in DOCK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-27). AlphaMissense: likely pathogenic (0.9896); Very rare (popmax 0.00534%, nfe); Associated with DOCK2 deficiency.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00534%, nfe)

## For patients & families {#patients}

This is a change in the DOCK2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, 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.Asp598Val |
| Coding change (HGVS c.) | c.1793A>T |
| MANE Select transcript | [NM_004946](https://www.ncbi.nlm.nih.gov/nuccore/NM_004946) |
| Variant type | single nucleotide variant |
| Location | chr5:169714161-169714161 (GRCh38) |
| ClinVar | [VCV4243838](https://www.ncbi.nlm.nih.gov/clinvar/variation/4243838/) |

**All HGVS expressions:** `LRG_1227:g.81915A>T`, `LRG_1227t1:c.1793A>T`, `NC_000005.10:g.169714161A>T`, `NC_000005.9:g.169141165A>T`, `NG_051800.1:g.81915A>T`, `NM_004946.3:c.1793A>T`, `NR_156756.1:n.1845A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9896)
- REVEL 0.714 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.946 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.166, GERP 2.42, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in DOCK2 (of 10,859 modeled).
- CADD: **PHRED 27.9**. 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 0.72** across the covering region of the MANE Select transcript (169,702,316–170,050,309), spanning 347,993 bp. Chi-square p 3.1e-21. 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 (A>G, Δ0.35 donor 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 **0.00534%** (nfe) · FAF95 0.00427% · FAF99 0.00388% · 63/1,179,626 in the highest group · 64/1,613,306 alleles overall — very rare (popmax 0.00534%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00534% | 18,724 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,464 |

*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}

Residue **598** lies in the c2 dock-type domain.

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. p.Asp598Val falls in the c2 dock-type domain. 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-27.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-27 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related DOCK2 variant pages (same residue, condition, or type): [DOCK2 c.2267+3G>A](/variant/dock2-c-2267-plus-3g-a), [DOCK2 c.2704-3C>T](/variant/dock2-c-2704-minus-3c-t), [DOCK2 c.4467+4A>G](/variant/dock2-c-4467-plus-4a-g), [DOCK2 p.Ala1393Val](/variant/dock2-p-ala1393val), [DOCK2 p.Ala1710Val](/variant/dock2-p-ala1710val), [DOCK2 p.Ala1765Val](/variant/dock2-p-ala1765val), [DOCK2 p.Ala24Pro](/variant/dock2-p-ala24pro), [DOCK2 p.Ala454Val](/variant/dock2-p-ala454val).

### 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 4243838). 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.*