Is DOK7 p.Ser422fs (c.1263dup) pathogenic?

DOK7 p.Ser422fs (c.1263dup) is classified Pathogenic/Likely pathogenic in DOK7 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-05). Ultra-rare (popmax 0.028%, afr); Associated with congenital myasthenic syndrome 10.

What condition is associated with DOK7 p.Ser422fs (c.1263dup)?

DOK7 p.Ser422fs (c.1263dup) is associated with congenital myasthenic syndrome 10, Rett syndrome, congenital myasthenic syndrome (ClinVar).

How common is DOK7 p.Ser422fs (c.1263dup) in the general population?

DOK7 p.Ser422fs (c.1263dup) is ultra-rare (popmax 0.028%, afr) (gnomAD).

DOK7 p.Ser422fs

c.1263dup · rs606231129 · VCV1274

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, afr)

Conditions

congenital myasthenic syndrome 10

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (7 of 7) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.72	GERP -0.27
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.028% African / African-American · 21/74,918 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.0123% 198/1,611,824 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.028%	3,568
European (non-Finnish)	0.0141%	7,106
Remaining individualsnot grpmax-eligible	0.0112%	8,914
South Asian	0.0044%	22,752

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.Ser422fs
Coding: c.1263dup
MANE Select: NM_173660
dbSNP: rs606231129
Type: Duplication
Location: chr4:3493242 (GRCh38)
Gene constraint: LOEUF 1.658 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.61
Residue 422: the 'disordered' region

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

Disease context

congenital myasthenic syndrome 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Rett syndrome congenital myasthenic syndrome fetal akinesia deformation sequence 1 fetal akinesia deformation sequence 3

Similar variants

DOK7 p.Ala378fs Pathogenic ★★ same condition
DOK7 p.Ala380fs Pathogenic ★★ same condition
DOK7 p.Gln460fs Pathogenic/Likely pathogenic ★★ same condition
DOK7 p.Glu382fs Pathogenic/Likely pathogenic ★★ same condition
DOK7 p.Gly496fs Pathogenic/Likely pathogenic ★★ same condition
DOK7 p.His481fs Pathogenic/Likely pathogenic ★★ same condition
DOK7 p.Ser338fs Pathogenic/Likely pathogenic ★★ same condition
DOK7 c.54+32_54+33dup Benign/Likely benign ★★ 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-ser422fs (accessed [today's date]).

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