Is DOK7 p.Ala378fs (c.1124_1127dup) pathogenic?

DOK7 p.Ala378fs (c.11241127dup) is classified Pathogenic in DOK7 (ClinVar, Multiple submitters, 38 submitters; last evaluated 2026-04-01). Rare (popmax 0.134%, nfe); Associated with Fetal anomalies with a likely genetic cause.

What condition is associated with DOK7 p.Ala378fs (c.1124_1127dup)?

DOK7 p.Ala378fs (c.1124_1127dup) is associated with Fetal anomalies with a likely genetic cause, congenital myasthenic syndrome 10, Ritscher-Schinzel syndrome 2 (ClinVar).

How common is DOK7 p.Ala378fs (c.1124_1127dup) in the general population?

DOK7 p.Ala378fs (c.1124_1127dup) is rare (popmax 0.134%, nfe) (gnomAD).

DOK7 p.Ala378fs

c.1124_1127dup · rs606231128 · VCV1273

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 38 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.134%, nfe)

Conditions

Fetal anomalies with a likely genetic cause

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 7.4	GERP -0.01, phastCons 1
Overall
CADD	33.0	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 0.134% European (non-Finnish) · 1,572/1,169,026 alleles

Filtering AF 0.129% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.127%

Overall 0.111% 1,766/1,584,152 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.134%	744
Remaining individualsnot grpmax-eligible	0.096%	1,042
South Asian	0.0796%	1,256
Admixed American	0.0763%	1,311
African / African-American	0.0201%	4,972
Middle Eastern	0.0166%	6,038
Finnishnot grpmax-eligible	0.0108%	9,278

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.Ala378fs
Coding: c.1124_1127dup
MANE Select: NM_173660
dbSNP: rs606231128
Type: Duplication
Location: chr4:3493106 (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 anomalies with a likely genetic cause

Also linked: congenital myasthenic syndrome 10 Ritscher-Schinzel syndrome 2 congenital myasthenic syndrome fetal akinesia deformation sequence 1 fetal akinesia deformation sequence 3

Similar variants

DOK7 p.Ala378= Benign/Likely benign ★★ same residue
DOK7 p.Ala378Val Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-ala378fs (accessed [today's date]).

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