# NM_001363540.2(DOCK4):c.892C>T (p.Arg298Ter)

https://sugi.bio/variant/dock4-p-arg298ter

## Summary

**DOCK4 p.Arg298Ter (c.892C>T)** is classified **Uncertain significance** in DOCK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-12). Very rare (popmax 0.00017%, nfe); Associated with neurodevelopmental disorder.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1413830150 · 1 submitter · 1 linked condition · very rare (popmax 0.00017%, nfe)

## 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 neurodevelopmental 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.*

|  |  |
| --- | --- |
| Clinical trials | 210 registered for this condition — see ClinicalTrials.gov |

**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.Arg298Ter |
| Coding change (HGVS c.) | c.892C>T |
| MANE Select transcript | [NM_001363540](https://www.ncbi.nlm.nih.gov/nuccore/NM_001363540) |
| dbSNP | [rs1413830150](https://www.ncbi.nlm.nih.gov/snp/rs1413830150/) |
| Variant type | single nucleotide variant |
| Location | chr7:111940195-111940195 (GRCh38) |
| ClinVar | [VCV2627580](https://www.ncbi.nlm.nih.gov/clinvar/variation/2627580/) |

**All HGVS expressions:** `NC_000007.13:g.111580250G>A`, `NC_000007.14:g.111940195G>A`, `NG_028060.2:g.271217C>T`, `NM_001363540.2:c.892C>T`, `NM_014705.4:c.892C>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 7.488, 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 40.0**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,890 in the highest group · 2/1,461,708 alleles overall — very rare (popmax 0.00017%, nfe).

*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 2024-02-12.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, University of Leipzig Medical Center | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-12 |

## Associated conditions {#conditions}

[neurodevelopmental disorder](https://sugi.bio/atlas/disease/neurodevelopmental-disorder/).

**Reported phenotype names (ClinVar):** Neurodevelopmental disorder.

## Similar variants {#similar}

Related DOCK4 variant pages (same residue, condition, or type): [DOCK4 p.Ile1067Thr](/variant/dock4-p-ile1067thr), [DOCK4 p.Met1044Thr](/variant/dock4-p-met1044thr), [DOCK4 p.Thr982Ile](/variant/dock4-p-thr982ile), [DOCK4 p.Arg1347Gln](/variant/dock4-p-arg1347gln), [DOCK4 p.Arg924Ter](/variant/dock4-p-arg924ter), [DOCK4 p.Lys1971Asn](/variant/dock4-p-lys1971asn), [DOCK4 p.Pro253Leu](/variant/dock4-p-pro253leu), [DOCK4 p.Trp1464Ter](/variant/dock4-p-trp1464ter).

### 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 2627580). 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.*