Is DOK7 p.Arg409Cys (c.1225C>T) pathogenic?

DOK7 p.Arg409Cys (c.1225C>T) is classified Uncertain significance in DOK7 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-02). AlphaMissense: likely benign (0.1837); Ultra-rare (popmax 0.0423%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DOK7 p.Arg409Cys (c.1225C>T)?

DOK7 p.Arg409Cys (c.1225C>T) is associated with Inborn genetic diseases, congenital myasthenic syndrome 10, fetal akinesia deformation sequence 1 (ClinVar).

How common is DOK7 p.Arg409Cys (c.1225C>T) in the general population?

DOK7 p.Arg409Cys (c.1225C>T) is ultra-rare (popmax 0.0423%, nfe) (gnomAD).

What do computational predictors say about DOK7 p.Arg409Cys (c.1225C>T)?

AlphaMissense predicts likely benign (score 0.1837) — an in-silico prediction, not a clinical call.

DOK7 p.Arg409Cys

c.1225C>T · rs199606134 · VCV534126

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1837 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0423%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1837	likely benign
REVEL	0.468	indeterminate
SaProt	LLR -10.24	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP -0.12, phastCons 0.98
Regional constraint	o/e 1.44	unconstrained · MANE · 30 kb · p 2.5e-31 · regional, not allelic
Overall
CADD	24.6	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 0.0423% European (non-Finnish) · 499/1,179,644 alleles

Filtering AF 0.0392% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.038%

Overall 0.0334% 538/1,611,724 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0423%	2,364
Remaining individualsnot grpmax-eligible	0.024%	4,161
African / African-American	0.012%	8,324
East Asian	0.0111%	8,971
Admixed American	0.01%	9,988
Finnishnot grpmax-eligible	0.0032%	31,228
South Asian	0.0022%	45,476

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.Arg409Cys
Coding: c.1225C>T
MANE Select: NM_173660
dbSNP: rs199606134
Type: single nucleotide variant
Location: chr4:3493211 (GRCh38)
Gene constraint: LOEUF 1.658 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.61

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myasthenic syndrome 10 fetal akinesia deformation sequence 1

Similar variants

DOK7 p.Arg409His Uncertain significance ★★ ⚠ same residue
DOK7 p.Arg409= Likely benign ★ 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

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-arg409cys (accessed [today's date]).

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