Is DOK7 p.Asp433fs (c.1296_1311del) pathogenic?

DOK7 p.Asp433fs (c.12961311del) is classified Pathogenic/Likely pathogenic in DOK7 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-30). Ultra-rare (popmax 0.0156%, eas); Associated with fetal akinesia deformation sequence 3.

What condition is associated with DOK7 p.Asp433fs (c.1296_1311del)?

DOK7 p.Asp433fs (c.1296_1311del) is associated with fetal akinesia deformation sequence 3, congenital myasthenic syndrome 10, fetal akinesia deformation sequence 1 (ClinVar).

How common is DOK7 p.Asp433fs (c.1296_1311del) in the general population?

DOK7 p.Asp433fs (c.1296_1311del) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

DOK7 p.Asp433fs

c.1296_1311del · rs778172294 · VCV813360

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Conditions

fetal akinesia deformation sequence 3

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 -6	GERP -2
Overall
CADD	32.0	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 0.0156% East Asian · 7/44,840 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00248% 40/1,611,174 alleles · ultra-rare exomes 35/1,458,892 · genomes 5/152,282 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,406
African / African-American	0.00666%	15,005
Remaining individualsnot grpmax-eligible	0.00321%	31,179
European (non-Finnish)	0.00204%	49,138
Admixed American	0.00167%	59,914
South Asian	0.0011%	90,870

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.Asp433fs
Coding: c.1296_1311del
MANE Select: NM_173660
dbSNP: rs778172294
Type: Deletion
Location: chr4:3493274 (GRCh38)
Gene constraint: LOEUF 1.658 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.61
Residue 433: the 'disordered' region

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

Disease context

fetal akinesia deformation sequence 3 — 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.Asp433His Uncertain significance ★ same residue
DOK7 c.54+25_55-38del Pathogenic/Likely pathogenic ★★ same condition
DOK7 p.Cys442fs Pathogenic/Likely pathogenic ★★ same condition
DOK7 p.Ile199fs Pathogenic/Likely pathogenic ★★ same condition
DOK7 p.Leu454fs Pathogenic/Likely pathogenic ★★ same condition
DOK7 p.Leu466fs Pathogenic/Likely pathogenic ★★ same condition
DOK7 p.Lys320fs Pathogenic ★★ same condition
DOK7 p.Pro415fs Pathogenic/Likely 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-asp433fs (accessed [today's date]).

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