# NM_020812.4(DOCK6):c.4531_4532del (p.Ser1511fs)

https://sugi.bio/variant/dock6-p-ser1511fs

## Summary

**DOCK6 p.Ser1511fs (c.4531_4532del)** is classified **Likely pathogenic** in DOCK6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-04). Very rare (popmax 0.00267%, afr); Associated with Adams-Oliver syndrome 2.

**At a glance:** Likely pathogenic · review: Multiple submitters · 2 submitters · 2 linked conditions · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the DOCK6 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to Adams-Oliver syndrome 2.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015775/index) · [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.Ser1511fs |
| Coding change (HGVS c.) | c.4531_4532del |
| MANE Select transcript | [NM_020812](https://www.ncbi.nlm.nih.gov/nuccore/NM_020812) |
| Variant type | Microsatellite |
| Location | chr19:11212111-11212112 (GRCh38) |
| ClinVar | [VCV3779280](https://www.ncbi.nlm.nih.gov/clinvar/variation/3779280/) |

**All HGVS expressions:** `NC_000019.10:g.11212111GA[3]`, `NC_000019.9:g.11322787GA[3]`, `NG_031953.1:g.55375TC[3]`, `NM_001367830.1:c.4636_4637del`, `NM_020812.4:c.4531_4532del`, `NM_020812.4:c.4531_4532delTC`

## 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 -20, GERP -5.05 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.87, pLI 1.38e-40. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 36 of 48**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 35.0**. 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** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00267%** (afr) · FAF95 0.000763% · FAF99 0.000605% · 2/74,820 in the highest group · 18/1,611,918 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00267% | 37,410 |
| European (non-Finnish) | 0.00127% | 78,645 |
| South Asian | 0.0011% | 90,920 |

*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}


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}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-04.

**Submitter consensus:** unanimous (2/2 Likely pathogenic).

**Submission history:** 2 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely pathogenic | criteria provided, single submitter | research | 2021-09-17 |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-06-04 |

## Associated conditions {#conditions}

[Adams-Oliver syndrome 2](https://sugi.bio/atlas/disease/adams-oliver-syndrome-2/), [Adams-Oliver syndrome](https://sugi.bio/atlas/disease/adams-oliver-syndrome/).

**Reported phenotype names (ClinVar):** Adams-Oliver syndrome 2, Adams-Oliver syndrome.

## Similar variants {#similar}

Related DOCK6 variant pages (same residue, condition, or type): [DOCK6 p.Leu207fs](/variant/dock6-p-leu207fs), [DOCK6 p.Lys1928fs](/variant/dock6-p-lys1928fs), [DOCK6 p.Ser1511=](/variant/dock6-p-ser1511), [DOCK6 c.5939+2T>C](/variant/dock6-c-5939-plus-2t-c), [DOCK6 c.807-1G>A](/variant/dock6-c-807-minus-1g-a), [DOCK6 p.Arg1526Ter](/variant/dock6-p-arg1526ter), [DOCK6 p.Arg184Ter](/variant/dock6-p-arg184ter), [DOCK6 p.Arg488Ter](/variant/dock6-p-arg488ter).

### 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 3779280). 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.*