# NM_001363540.2(DOCK4):c.847C>T (p.Arg283Ter)

https://sugi.bio/variant/dock4-p-arg283ter

## Summary

**DOCK4 p.Arg283Ter (c.847C>T)** is classified **Uncertain significance** in DOCK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-05). Absent from gnomAD v4.1; Associated with DOCK4-related disorder.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DOCK4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to DOCK4-related disorder.

*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 | [DOCK4](https://sugi.bio/atlas/gene/DOCK4/) |
| Protein change (HGVS p.) | p.Arg283Ter |
| Coding change (HGVS c.) | c.847C>T |
| MANE Select transcript | [NM_001363540](https://www.ncbi.nlm.nih.gov/nuccore/NM_001363540) |
| Variant type | single nucleotide variant |
| Location | chr7:111940240-111940240 (GRCh38) |
| ClinVar | [VCV4853908](https://www.ncbi.nlm.nih.gov/clinvar/variation/4853908/) |

**All HGVS expressions:** `NC_000007.13:g.111580295G>A`, `NC_000007.14:g.111940240G>A`, `NG_028060.2:g.271172C>T`, `NM_001363540.2:c.847C>T`, `NM_014705.4:c.847C>T`

## Computational & population evidence {#evidence}

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

- **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 8.583, GERP 1.89, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.445, pLI 0.9999), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 11 of 53**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 42.0**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.25 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**DOCK4** population constraint: LOEUF 0.445, pLI 0.9999, missense-Z 1.6961. *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 76.47, 37% of residues very-high.

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

*Describes the biological roles of DOCK4 (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:** DOCK4's established molecular role includes guanyl-nucleotide exchange factor activity.


### Pathways affected {#pathways}

DOCK4 participates in **4 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 |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | 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, PDZ domain binding, receptor tyrosine kinase binding, small GTPase binding.

**Biological process:** cell chemotaxis, 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 2026-01-05.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-05 |

## Associated conditions {#conditions}

[DOCK4-related disorder](https://sugi.bio/atlas/disease/dock4-related-disorder/).

**Reported phenotype names (ClinVar):** DOCK4-related disorder, DOCK4-related condition.

## Similar variants {#similar}

Related DOCK4 variant pages (same residue, condition, or type): [DOCK4 c.1192+9C>G](/variant/dock4-c-1192-plus-9c-g), [DOCK4 p.Arg1429Gln](/variant/dock4-p-arg1429gln), [DOCK4 p.Pro1835Leu](/variant/dock4-p-pro1835leu), [DOCK4 c.3316-10T>G](/variant/dock4-c-3316-minus-10t-g), [DOCK4 c.4417-2A>G](/variant/dock4-c-4417-minus-2a-g), [DOCK4 p.Gln1498Ter](/variant/dock4-p-gln1498ter), [DOCK4 p.Gly1038Ser](/variant/dock4-p-gly1038ser), [DOCK4 p.Pro1800Ser](/variant/dock4-p-pro1800ser).

### 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 4853908). 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.*