# NM_173660.5(DOK7):c.1351C>T (p.Arg451Trp)

https://sugi.bio/variant/dok7-p-arg451trp

## Summary

**DOK7 p.Arg451Trp (c.1351C>T)** is classified **Benign** in DOK7 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1141); Low-frequency (popmax 4.2%, afr); Associated with fetal akinesia deformation sequence 1.

**At a glance:** Benign · review: Multiple submitters · rsID rs16844470 · 7 submitters · 2 linked conditions · AlphaMissense likely benign · low-frequency (popmax 4.2%, afr)

## For patients & families {#patients}

This is a change in the DOK7 gene that is classified as benign — not considered disease-causing, submitted by 7 submitters, and is linked to fetal akinesia deformation sequence 1.

*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/0026048/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.Arg451Trp |
| Coding change (HGVS c.) | c.1351C>T |
| MANE Select transcript | [NM_173660](https://www.ncbi.nlm.nih.gov/nuccore/NM_173660) |
| dbSNP | [rs16844470](https://www.ncbi.nlm.nih.gov/snp/rs16844470/) |
| Variant type | single nucleotide variant |
| Location | chr4:3493337-3493337 (GRCh38) |
| ClinVar | [VCV128910](https://www.ncbi.nlm.nih.gov/clinvar/variation/128910/) |

**All HGVS expressions:** `LRG_869:g.35032C>T`, `LRG_869t1:c.1351C>T`, `NC_000004.11:g.3495064C>T`, `NC_000004.12:g.3493337C>T`, `NG_013072.2:g.35032C>T`, `NM_001164673.2:c.*572C>T`, `NM_001256896.2:c.421C>T`, `NM_001301071.2:c.1351C>T`, `NM_001363811.2:c.919C>T`, `NM_173660.5:c.1351C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1141)
- REVEL 0.151 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.87 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.09, GERP 1.02 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 22.5**. 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 1.44** across the covering region of the MANE Select transcript (3,463,376–3,493,498), spanning 30,122 bp. Chi-square p 2.5e-31. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **4.2%** (afr) · FAF95 4.08% · FAF99 4.03% · 3,139/74,768 in the highest group · 5,217/1,600,082 alleles overall — low-frequency (popmax 4.2%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 4.2% | 24 |
| Admixed American | 0.553% | 181 |
| Remaining individuals (not grpmax-eligible) | 0.395% | 253 |
| Middle Eastern | 0.182% | 549 |
| European (non-Finnish) | 0.123% | 812 |
| South Asian | 0.0502% | 1,994 |
| Finnish (not grpmax-eligible) | 0.00978% | 10,221 |
| East Asian | 0.00677% | 14,773 |

*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 30, triplosensitivity Not yet evaluated (0–3 scale). *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}

Residue **451** lies in a UniProt-annotated variant site (in); the 'disordered' region.

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. p.Arg451Trp falls in the disordered region.


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

**Molecular function:** protein kinase binding.

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

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (6 Benign, 1 Likely benign).

**Submission history:** 7 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2014-12-16 |
| Genetic Services Laboratory, University of Chicago | Likely benign | no assertion criteria provided | clinical testing |  |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2017-08-03 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2023-09-26 |

## Associated conditions {#conditions}

[fetal akinesia deformation sequence 1](https://sugi.bio/atlas/disease/fetal-akinesia-deformation-sequence-1/), [congenital myasthenic syndrome 10](https://sugi.bio/atlas/disease/congenital-myasthenic-syndrome-10/).

**Reported phenotype names (ClinVar):** Fetal akinesia deformation sequence 1, not specified, Congenital myasthenic syndrome 10, not provided, Fetal akinesia sequence, Pena-Shokeir syndrome type I, Myasthenia, limb-girdle, familial, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related DOK7 variant pages (same residue, condition, or type): [DOK7 p.Arg451Gln](/variant/dok7-p-arg451gln), [DOK7 c.331+1G>T](/variant/dok7-c-331-plus-1g-t), [DOK7 c.332-1G>A](/variant/dok7-c-332-minus-1g-a), [DOK7 c.332-1G>C](/variant/dok7-c-332-minus-1g-c), [DOK7 c.332-1G>T](/variant/dok7-c-332-minus-1g-t), [DOK7 p.Arg158Gln](/variant/dok7-p-arg158gln), [DOK7 p.Arg201Ter](/variant/dok7-p-arg201ter), [DOK7 p.Cys412Ter](/variant/dok7-p-cys412ter).

### 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 128910). 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.*