# NM_020812.4(DOCK6):c.452G>T (p.Arg151Leu)

https://sugi.bio/variant/dock6-p-arg151leu

## Summary

**DOCK6 p.Arg151Leu (c.452G>T)** is classified **Uncertain significance** in DOCK6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-13). AlphaMissense: likely benign (0.1734); Ultra-rare (popmax 0.0276%, eas); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs374746195 · 3 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0276%, eas)

## For patients & families {#patients}

This is a change in the DOCK6 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to Inborn genetic diseases.

*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 | [DOCK6](https://sugi.bio/atlas/gene/DOCK6/) |
| Protein change (HGVS p.) | p.Arg151Leu |
| Coding change (HGVS c.) | c.452G>T |
| MANE Select transcript | [NM_020812](https://www.ncbi.nlm.nih.gov/nuccore/NM_020812) |
| dbSNP | [rs374746195](https://www.ncbi.nlm.nih.gov/snp/rs374746195/) |
| Variant type | single nucleotide variant |
| Location | chr19:11252174-11252174 (GRCh38) |
| ClinVar | [VCV2191426](https://www.ncbi.nlm.nih.gov/clinvar/variation/2191426/) |

**All HGVS expressions:** `NC_000019.10:g.11252174C>A`, `NC_000019.9:g.11362850C>A`, `NG_031953.1:g.15319G>T`, `NM_001367830.1:c.452G>T`, `NM_020812.2:c.452G>T`, `NM_020812.3:c.452G>T`, `NM_020812.4:c.452G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1734)
- REVEL 0.079 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.429 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.29) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.365, GERP -2.83, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 20.9**. 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 0.92** across the covering region of the MANE Select transcript (11,199,500–11,262,440), spanning 62,940 bp. Chi-square p 1.8e-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 **0.02**, donor loss **0.01**, acceptor gain **0.29**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.02**, donor loss **0.01**, acceptor gain **0.29**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0276%** (eas) · FAF95 0.0159% · FAF99 0.0125% · 12/43,444 in the highest group · 16/1,584,230 alleles overall — ultra-rare (popmax 0.0276%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0276% | 3,620 |
| Remaining individuals (not grpmax-eligible) | 0.00163% | 61,464 |
| African / African-American | 0.00135% | 74,314 |
| European (non-Finnish) | 0.000172% | 582,761 |

*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}

**DOCK6** population constraint: LOEUF 0.87, pLI 1.38e-40, missense-Z 0.83921. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Adams-Oliver syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **151** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 77.78, 30% of residues very-high.

**7 experimental structure(s)** (PDB): [9VM2](https://www.rcsb.org/structure/9VM2), [9VM3](https://www.rcsb.org/structure/9VM3), [9VM4](https://www.rcsb.org/structure/9VM4), [9VM5](https://www.rcsb.org/structure/9VM5), [9VM6](https://www.rcsb.org/structure/9VM6), [9VM7](https://www.rcsb.org/structure/9VM7).

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

*Describes the biological roles of DOCK6 (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}

DOCK6 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [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 |

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-02-13.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-13 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-03-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-11-02 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, DOCK6-related disorder, DOCK6-related condition, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related DOCK6 variant pages (same residue, condition, or type): [DOCK6 p.Arg151Cys](/variant/dock6-p-arg151cys), [DOCK6 p.Arg151His](/variant/dock6-p-arg151his), [DOCK6 p.Arg151Gly](/variant/dock6-p-arg151gly), [DOCK6 c.5939+2T>C](/variant/dock6-c-5939-plus-2t-c), [DOCK6 p.Glu1494Ter](/variant/dock6-p-glu1494ter), [DOCK6 p.Ala1153Thr](/variant/dock6-p-ala1153thr), [DOCK6 p.Ala1207Val](/variant/dock6-p-ala1207val), [DOCK6 p.Ala1241Thr](/variant/dock6-p-ala1241thr).

### 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 2191426). 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.*