Is DOK7 p.Arg451Trp (c.1351C>T) pathogenic?

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.

What condition is associated with DOK7 p.Arg451Trp (c.1351C>T)?

DOK7 p.Arg451Trp (c.1351C>T) is associated with fetal akinesia deformation sequence 1, congenital myasthenic syndrome 10 (ClinVar).

How common is DOK7 p.Arg451Trp (c.1351C>T) in the general population?

DOK7 p.Arg451Trp (c.1351C>T) is low-frequency (popmax 4.2%, afr) (gnomAD).

What do computational predictors say about DOK7 p.Arg451Trp (c.1351C>T)?

AlphaMissense predicts likely benign (score 0.1141) — an in-silico prediction, not a clinical call.

DOK7 p.Arg451Trp

c.1351C>T · rs16844470 · VCV128910

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1141 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.2%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

fetal akinesia deformation sequence 1

Computational evidence

Protein change
AlphaMissense	0.1141	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -7.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.09	GERP 1
Regional constraint	o/e 1.44	unconstrained · MANE · 30 kb · p 2.5e-31 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.2% African / African-American · 3,139/74,768 alleles

Filtering AF 4.08% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.03%

Overall 0.326% 5,217/1,600,082 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.2%	24
Admixed American	0.553%	181
Remaining individualsnot grpmax-eligible	0.395%	253
Middle Eastern	0.182%	549
European (non-Finnish)	0.123%	812
South Asian	0.0502%	1,994
Finnishnot grpmax-eligible	0.00978%	10,221
East Asian	0.00677%	14,773

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DOK7
Protein: p.Arg451Trp
Coding: c.1351C>T
MANE Select: NM_173660
dbSNP: rs16844470
Type: single nucleotide variant
Location: chr4:3493337 (GRCh38)
Gene constraint: LOEUF 1.658 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.61
Residue 451: a UniProt-annotated variant site (in); the 'disordered' region

Full DOK7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

fetal akinesia deformation sequence 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myasthenic syndrome 10

Similar variants

DOK7 p.Arg451Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
DOK7 c.331+1G>T Pathogenic ★★ same condition
DOK7 c.332-1G>A Likely pathogenic ★★ same condition
DOK7 c.332-1G>C Likely pathogenic ★★ same condition
DOK7 c.332-1G>T Likely pathogenic ★★ same condition
DOK7 p.Arg158Gln Pathogenic/Likely pathogenic ★★ same condition
DOK7 p.Arg201Ter Pathogenic ★★ same condition
DOK7 p.Cys412Ter Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dok7-p-arg451trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown