# NM_001363540.2(DOCK4):c.4988T>C (p.Val1663Ala)

https://sugi.bio/variant/dock4-p-val1663ala

## Summary

**DOCK4 p.Val1663Ala (c.4988T>C)** is classified **Uncertain significance** in DOCK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-03). AlphaMissense: likely benign (0.2565); Very rare (popmax 0.005%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.005%, 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.

*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.Val1663Ala |
| Coding change (HGVS c.) | c.4988T>C |
| MANE Select transcript | [NM_001363540](https://www.ncbi.nlm.nih.gov/nuccore/NM_001363540) |
| Variant type | single nucleotide variant |
| Location | chr7:111741146-111741146 (GRCh38) |
| ClinVar | [VCV3504448](https://www.ncbi.nlm.nih.gov/clinvar/variation/3504448/) |

**All HGVS expressions:** `NC_000007.13:g.111381202A>G`, `NC_000007.14:g.111741146A>G`, `NG_028060.2:g.470266T>C`, `NM_001363540.2:c.4988T>C`, `NM_014705.4:c.4961T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2565)
- REVEL 0.239 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.008 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.41) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.256, GERP 2.74, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **V1654A** vs ClinVar **V1663A**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 24.0**. 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.*
- Regional missense constraint: **o/e 1.17** across the covering region of the MANE Select transcript (111,728,277–111,741,619), spanning 13,342 bp. Chi-square p 0.00031. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.41**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 2 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.*
- Population frequency (gnomAD v4.1): grpmax **0.005%** (nfe) · FAF95 0.00394% · FAF99 0.00361% · 59/1,179,902 in the highest group · 61/1,613,924 alleles overall — very rare (popmax 0.005%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.005% | 19,998 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,464 |
| African / African-American | 0.00133% | 74,936 |

*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}

Residue **1654** lies in the 'disordered' region.

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. p.Val1663Ala falls in the disordered region.


### 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 2024-10-03.

**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 | 2024-10-03 |

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

## Similar variants {#similar}

Related DOCK4 variant pages (same residue, condition, or type): [DOCK4 p.Arg490Trp](/variant/dock4-p-arg490trp), [DOCK4 p.Gln1223Arg](/variant/dock4-p-gln1223arg), [DOCK4 p.His1716Tyr](/variant/dock4-p-his1716tyr), [DOCK4 p.Pro1641Leu](/variant/dock4-p-pro1641leu), [DOCK4 p.Ser750Arg](/variant/dock4-p-ser750arg), [DOCK4 c.550-8T>C](/variant/dock4-c-550-minus-8t-c), [DOCK4 p.Arg106Cys](/variant/dock4-p-arg106cys), [DOCK4 p.Arg106His](/variant/dock4-p-arg106his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 3504448). 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.*