Is DOK7 p.Pro486fs (c.1457del) pathogenic?

DOK7 p.Pro486fs (c.1457del) is classified Conflicting classifications of pathogenicity in DOK7 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-02-02). Very rare (popmax 0.00168%, amr); Associated with fetal akinesia deformation sequence 3.

What condition is associated with DOK7 p.Pro486fs (c.1457del)?

DOK7 p.Pro486fs (c.1457del) is associated with fetal akinesia deformation sequence 3, congenital myasthenic syndrome 10, congenital myasthenic syndrome (ClinVar).

How common is DOK7 p.Pro486fs (c.1457del) in the general population?

DOK7 p.Pro486fs (c.1457del) is very rare (popmax 0.00168%, amr) (gnomAD).

DOK7 p.Pro486fs

c.1457del · rs1577184455 · VCV689376

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

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 -3.1	GERP -1.6
Overall
CADD	14.58	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 0.00168% Admixed American · 1/59,464 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000498% 8/1,606,370 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00168%	59,464
European (non-Finnish)	0.000595%	168,136

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.Pro486fs
Coding: c.1457del
MANE Select: NM_173660
dbSNP: rs1577184455
Type: Deletion
Location: chr4:3493439 (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

fetal akinesia deformation sequence 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

DOK7 p.Pro486Leu Uncertain significance ★★ ⚠ same residue
DOK7 p.Pro486= Likely benign ★ same residue
DOK7 c.54+25_55-38del Pathogenic/Likely pathogenic ★★ same condition
DOK7 p.Asp433fs 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

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-pro486fs (accessed [today's date]).

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