# NM_024940.8(DOCK5):c.1653C>T (p.Phe551=)

https://sugi.bio/variant/dock5-p-phe551

## Summary

**DOCK5 p.Phe551= (c.1653C>T)** is classified **Likely benign** in DOCK5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-01). Ultra-rare (popmax 0.0413%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs146969490 · 1 submitter · ultra-rare (popmax 0.0413%, nfe)

## For patients & families {#patients}

This is a change in the DOCK5 gene that is classified as likely benign — not considered disease-causing, 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.Phe551= |
| Coding change (HGVS c.) | c.1653C>T |
| MANE Select transcript | [NM_024940](https://www.ncbi.nlm.nih.gov/nuccore/NM_024940) |
| dbSNP | [rs146969490](https://www.ncbi.nlm.nih.gov/snp/rs146969490/) |
| Variant type | single nucleotide variant |
| Location | chr8:25323885-25323885 (GRCh38) |
| ClinVar | [VCV2658491](https://www.ncbi.nlm.nih.gov/clinvar/variation/2658491/) |

**All HGVS expressions:** `NC_000008.10:g.25181401C>T`, `NC_000008.11:g.25323885C>T`, `NG_051765.1:g.144114C>T`, `NM_024940.8:c.1653C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.26) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -1.342, GERP -3.46 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.659**. 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 deltas (raw): acceptor loss **0.26**, donor loss **0.07**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 37 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 **0.0413%** (nfe) · FAF95 0.0382% · FAF99 0.037% · 487/1,179,734 in the highest group · 906/1,613,490 alleles overall — ultra-rare (popmax 0.0413%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.442% | 226 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.372% | 269 |
| European (non-Finnish) (grpmax) | 0.0413% | 2,422 |
| Remaining individuals (not grpmax-eligible) | 0.0352% | 2,840 |
| African / African-American | 0.004% | 25,003 |
| South Asian | 0.0011% | 90,926 |

Finnish 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}

**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}

Residue **551** lies in the c2 dock-type domain.

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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-10-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## 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 2026-10-14); 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 2026-07-14); 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 2658491). 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.*