# NM_001366683.2(DOCK9):c.3212T>C (p.Val1071Ala)

https://sugi.bio/variant/dock9-p-val1071ala

## Summary

**DOCK9 p.Val1071Ala (c.3212T>C)** is classified **Uncertain significance** in DOCK9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: ambiguous (0.4667); Very rare (popmax 0.00336%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00336%, amr)

## For patients & families {#patients}

This is a change in the DOCK9 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 | [DOCK9](https://sugi.bio/atlas/gene/DOCK9/) |
| Protein change (HGVS p.) | p.Val1071Ala |
| Coding change (HGVS c.) | c.3212T>C |
| MANE Select transcript | [NM_001366683](https://www.ncbi.nlm.nih.gov/nuccore/NM_001366683) |
| Variant type | single nucleotide variant |
| Location | chr13:98867499-98867499 (GRCh38) |
| ClinVar | [VCV4244078](https://www.ncbi.nlm.nih.gov/clinvar/variation/4244078/) |

**All HGVS expressions:** `NC_000013.10:g.99519753A>G`, `NC_000013.11:g.98867499A>G`, `NM_001130048.2:c.3212T>C`, `NM_001130049.2:c.3215T>C`, `NM_001130050.2:c.3212T>C`, `NM_001318849.2:c.3215T>C`, `NM_001366676.2:c.3248T>C`, `NM_001366677.2:c.3248T>C`, `NM_001366678.2:c.3248T>C`, `NM_001366679.2:c.3212T>C`, `NM_001366680.2:c.3212T>C`, `NM_001366681.2:c.3212T>C`, `NM_001366682.2:c.3212T>C`, `NM_001366683.2:c.3212T>C`, `NM_001366684.2:c.3212T>C`, `NM_015296.3:c.3215T>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4667) — no call either way
- REVEL 0.629 (indeterminate)
- SaProt LLR -8.693 (tolerated)
- Conservation: phyloP 11.214, GERP 2.85, phastCons 1 — highly conserved
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **V1072A** vs ClinVar **V1071A**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 23.6**. 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 0.87** across the covering region of the MANE Select transcript (98,837,515–98,977,909), spanning 140,394 bp. Chi-square p 1.2e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.66 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00336%** (amr) · FAF95 0.00232% · FAF99 0.00202% · 2/59,564 in the highest group · 48/1,611,950 alleles overall — very rare (popmax 0.00336%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00938% | 10,660 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,566 |
| Admixed American (grpmax) | 0.00336% | 29,782 |
| Remaining individuals (not grpmax-eligible) | 0.00321% | 31,183 |
| European (non-Finnish) | 0.00314% | 31,869 |

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}

**DOCK9** population constraint: LOEUF 0.425, pLI 1, missense-Z 3.4648. *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 79.68, 41% of residues very-high.

**4 experimental structure(s)** (PDB): [1WG7](https://www.rcsb.org/structure/1WG7), [2WM9](https://www.rcsb.org/structure/2WM9), [2WMN](https://www.rcsb.org/structure/2WMN), [2WMO](https://www.rcsb.org/structure/2WMO).

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

*Describes the biological roles of DOCK9 (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:** DOCK9's established molecular role includes cadherin binding.


### Pathways affected {#pathways}

DOCK9 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 |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** cadherin binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-13.

**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 | 2025-08-13 |

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

## Similar variants {#similar}

Related DOCK9 variant pages (same residue, condition, or type): [DOCK9 p.Ala434Val](/variant/dock9-p-ala434val), [DOCK9 p.Asn1709=](/variant/dock9-p-asn1709), [DOCK9 p.Cys2012=](/variant/dock9-p-cys2012), [DOCK9 p.Leu1435=](/variant/dock9-p-leu1435), [DOCK9 c.5023+908C>T](/variant/dock9-c-5023-plus-908c-t), [DOCK9 c.5023+919C>T](/variant/dock9-c-5023-plus-919c-t), [DOCK9 c.5023+952C>T](/variant/dock9-c-5023-plus-952c-t), [DOCK9 c.5367+706T>A](/variant/dock9-c-5367-plus-706t-a).

### 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 4244078). 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.*