# NM_173660.5(DOK7):c.1457dup (p.Ala487fs)

https://sugi.bio/variant/dok7-p-ala487fs

## Summary

**DOK7 p.Ala487fs (c.1457dup)** is classified **Likely pathogenic** in DOK7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-04). Associated with fetal akinesia deformation sequence 3.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the DOK7 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to fetal akinesia deformation sequence 3.

*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/0016496/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DOK7](https://sugi.bio/atlas/gene/DOK7/) |
| Protein change (HGVS p.) | p.Ala487fs |
| Coding change (HGVS c.) | c.1457dup |
| MANE Select transcript | [NM_173660](https://www.ncbi.nlm.nih.gov/nuccore/NM_173660) |
| Variant type | Duplication |
| Location | chr4:3493438-3493439 (GRCh38) |
| ClinVar | [VCV3384086](https://www.ncbi.nlm.nih.gov/clinvar/variation/3384086/) |

**All HGVS expressions:** `LRG_869:g.35138dup`, `LRG_869t1:c.1457dup`, `NC_000004.11:g.3495170dup`, `NC_000004.12:g.3493443dup`, `NG_013072.2:g.35138dup`, `NM_001164673.2:c.*678dup`, `NM_001256896.2:c.527dup`, `NM_001301071.2:c.1457dup`, `NM_001363811.2:c.1025dup`, `NM_173660.5:c.1457dup`

## 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 -3.082, GERP -1.63 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.658, pLI 2.311e-14. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (7 of 7)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**DOK7** population constraint: LOEUF 1.658, pLI 2.311e-14, missense-Z -4.997; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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):

- **congenital myasthenic syndrome 10** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 65.61, 38% of residues very-high.

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

*Describes the biological roles of DOK7 (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:** DOK7's established molecular role includes protein kinase binding.


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

**Molecular function:** protein kinase binding.

**Biological process:** positive regulation of protein tyrosine kinase activity.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-04.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Dubai Health Genomic Medicine Center, Dubai Health | Likely pathogenic | criteria provided, single submitter | research | 2024-10-04 |

## Associated conditions {#conditions}

[fetal akinesia deformation sequence 3](https://sugi.bio/atlas/disease/fetal-akinesia-deformation-sequence-3/).

**Reported phenotype names (ClinVar):** Fetal akinesia deformation sequence 3.

## Similar variants {#similar}

Related DOK7 variant pages (same residue, condition, or type): [DOK7 p.Ala378fs](/variant/dok7-p-ala378fs), [DOK7 p.Ala380fs](/variant/dok7-p-ala380fs), [DOK7 p.Gln460fs](/variant/dok7-p-gln460fs), [DOK7 p.Glu382fs](/variant/dok7-p-glu382fs), [DOK7 p.Ser338fs](/variant/dok7-p-ser338fs), [DOK7 p.Ser422fs](/variant/dok7-p-ser422fs), [DOK7 p.Gln10fs](/variant/dok7-p-gln10fs), [DOK7 p.His132fs](/variant/dok7-p-his132fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3384086). 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.*