# NM_024940.8(DOCK5):c.2374C>T (p.Arg792Cys)

https://sugi.bio/variant/dock5-p-arg792cys

## Summary

**DOCK5 p.Arg792Cys (c.2374C>T)** is classified **Uncertain significance** in DOCK5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-02). AlphaMissense: likely benign (0.1863); Very rare (popmax 0.0088%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.0088%, sas)

## For patients & families {#patients}

This is a change in the DOCK5 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [DOCK5](https://sugi.bio/atlas/gene/DOCK5/) |
| Protein change (HGVS p.) | p.Arg792Cys |
| Coding change (HGVS c.) | c.2374C>T |
| MANE Select transcript | [NM_024940](https://www.ncbi.nlm.nih.gov/nuccore/NM_024940) |
| Variant type | single nucleotide variant |
| Location | chr8:25340923-25340923 (GRCh38) |
| ClinVar | [VCV3273382](https://www.ncbi.nlm.nih.gov/clinvar/variation/3273382/) |

**All HGVS expressions:** `NC_000008.10:g.25198439C>T`, `NC_000008.11:g.25340923C>T`, `NG_051765.1:g.161152C>T`, `NM_024940.8:c.2374C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1863)
- REVEL 0.418 (indeterminate)
- SaProt LLR -11.252 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- SpliceAI predicts **acceptor loss** (Δ 0.41) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.645, GERP 1.94, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.8**. 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 0.91** across the covering region of the MANE Select transcript (25,304,270–25,411,295), spanning 107,025 bp. Chi-square p 5.5e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.41**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 46 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.45** (loss), gain 0.02 / loss 0.45. 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 **0.0088%** (sas) · FAF95 0.00437% · FAF99 0.00312% · 8/90,950 in the highest group · 22/1,613,438 alleles overall — very rare (popmax 0.0088%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0088% | 11,369 |
| African / African-American | 0.00534% | 18,726 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,456 |
| European (non-Finnish) | 0.000763% | 131,084 |

*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}

**DOCK5** population constraint: LOEUF 0.679, pLI 2.2949e-21, missense-Z 1.73. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.63, 41% of residues very-high.

**11 experimental structure(s)** (PDB): [7DPA](https://www.rcsb.org/structure/7DPA), [8JHK](https://www.rcsb.org/structure/8JHK), [8XM7](https://www.rcsb.org/structure/8XM7), [8ZJ2](https://www.rcsb.org/structure/8ZJ2), [8ZJI](https://www.rcsb.org/structure/8ZJI), [8ZJJ](https://www.rcsb.org/structure/8ZJJ).

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

*Describes the biological roles of DOCK5 (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.*


### Pathways affected {#pathways}

DOCK5 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | curated |

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

**Biological process:** positive regulation of epithelial cell migration, positive regulation of substrate adhesion-dependent cell spreading, negative regulation of vascular associated smooth muscle contraction, positive regulation of vascular associated smooth muscle cell migration.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-02.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-02 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related DOCK5 variant pages (same residue, condition, or type): [DOCK5 c.4788+9C>T](/variant/dock5-c-4788-plus-9c-t), [DOCK5 p.Leu986Phe](/variant/dock5-p-leu986phe), [DOCK5 p.Met987Leu](/variant/dock5-p-met987leu), [DOCK5 p.Pro1467=](/variant/dock5-p-pro1467), [DOCK5 p.Ser1306=](/variant/dock5-p-ser1306), [DOCK5 p.Thr469Met](/variant/dock5-p-thr469met), [DOCK5 p.Ala1067Val](/variant/dock5-p-ala1067val), [DOCK5 p.Ala1194Ser](/variant/dock5-p-ala1194ser).

### 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 3273382). 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.*