# NM_004946.3(DOCK2):c.321+87C>T

https://sugi.bio/variant/dock2-c-321-plus-87c-t

## Summary

**DOCK2 c.321+87C>T** is classified **Benign** in DOCK2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-01-24). Common (popmax 30.2%, sas) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Single submitter · rsID rs12656761 · 2 submitters · common (popmax 30.2%, sas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the DOCK2 gene that is classified as benign — not considered disease-causing, submitted by 2 submitters.

*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 | [DOCK2](https://sugi.bio/atlas/gene/DOCK2/) |
| Coding change (HGVS c.) | c.321+87C>T |
| MANE Select transcript | [NM_004946](https://www.ncbi.nlm.nih.gov/nuccore/NM_004946) |
| dbSNP | [rs12656761](https://www.ncbi.nlm.nih.gov/snp/rs12656761/) |
| Variant type | single nucleotide variant |
| Location | chr5:169671261-169671261 (GRCh38) |
| ClinVar | [VCV2688329](https://www.ncbi.nlm.nih.gov/clinvar/variation/2688329/) |

**All HGVS expressions:** `LRG_1227:g.39015C>T`, `LRG_1227t1:c.321+87C>T`, `NC_000005.10:g.169671261C>T`, `NC_000005.9:g.169098265C>T`, `NG_051800.1:g.39015C>T`, `NM_004946.3:c.321+87C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 30.2%, sas) — too common for a highly-penetrant pathogenic allele.

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.68) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -1.5, GERP -3.52 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 22.4**. 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.*
- Splice region: **deep intronic (+87 nt into the intron)**.
- Non-coding constraint (Gnocchi): **Z 3.49**, o/e 0.75 (1 kb window 169,671,000–169,672,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.68**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.68**.
- Pangolin: Δ**0.56** (gain), gain 0.56 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **30.2%** (sas) · FAF95 29.9% · FAF99 29.8% · 23,962/79,240 in the highest group · 295,093/1,250,614 alleles overall — common (popmax 30.2%, sas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 31.5% | 3 |
| South Asian (grpmax) | 30.2% | 3 |
| East Asian | 29.3% | 3 |
| European (non-Finnish) | 24.6% | 4 |
| Middle Eastern | 23.8% | 4 |
| Remaining individuals (not grpmax-eligible) | 23.6% | 4 |
| Finnish (not grpmax-eligible) | 21.5% | 5 |
| Ashkenazi Jewish (not grpmax-eligible) | 19.9% | 5 |
| Admixed American | 14.4% | 7 |
| African / African-American | 10.2% | 10 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-24.

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

**Submission history:** 5 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan | Benign | criteria provided, single submitter | clinical testing | 2024-01-24 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

**Reported phenotype names (ClinVar):** not specified, Malignant lymphoma, large B-cell, diffuse, AllHighlyPenetrant.

## 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 2688329). 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.*