Is DOK7 p.Arg174Ser (c.522G>C) pathogenic?

DOK7 p.Arg174Ser (c.522G>C) is classified Uncertain significance in DOK7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-24). AlphaMissense: likely pathogenic (0.9217); Very rare (popmax 0.00119%, nfe); Associated with fetal akinesia deformation sequence 1.

What condition is associated with DOK7 p.Arg174Ser (c.522G>C)?

DOK7 p.Arg174Ser (c.522G>C) is associated with fetal akinesia deformation sequence 1, congenital myasthenic syndrome 10 (ClinVar).

How common is DOK7 p.Arg174Ser (c.522G>C) in the general population?

DOK7 p.Arg174Ser (c.522G>C) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about DOK7 p.Arg174Ser (c.522G>C)?

AlphaMissense predicts likely pathogenic (score 0.9217) — an in-silico prediction, not a clinical call.

DOK7 p.Arg174Ser

c.522G>C · rs762376200 · VCV641729

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9217 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

fetal akinesia deformation sequence 1

Computational evidence

Protein change
AlphaMissense	0.9217	likely pathogenic · top 9% in DOK7
REVEL	0.672	pathogenic-leaning
SaProt	LLR -12.66	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.58	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 2.2	GERP -2.5, phastCons 1
Regional constraint	o/e 1.44	unconstrained · MANE · 30 kb · p 2.5e-31 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% European (non-Finnish) · 14/1,180,036 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000958% 14/1,461,576 alleles · very rare

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.Arg174Ser
Coding: c.522G>C
MANE Select: NM_173660
dbSNP: rs762376200
Type: single nucleotide variant
Location: chr4:3476532 (GRCh38)
Gene constraint: LOEUF 1.658 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.61
Residue 174: the irs-type ptb domain

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

Disease context

fetal akinesia deformation sequence 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myasthenic syndrome 10

Similar variants

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
DOK7 p.Cys412Ter Pathogenic ★★ same condition
DOK7 p.Gln151Ter 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-arg174ser (accessed [today's date]).

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