Is DOK7 p.Arg22Lys (c.65G>A) pathogenic?

DOK7 p.Arg22Lys (c.65G>A) is classified Uncertain significance in DOK7 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely pathogenic (0.8435); Very rare (popmax 0.00721%, sas); Associated with congenital myasthenic syndrome 10.

What condition is associated with DOK7 p.Arg22Lys (c.65G>A)?

DOK7 p.Arg22Lys (c.65G>A) is associated with congenital myasthenic syndrome 10, fetal akinesia deformation sequence 1 (ClinVar).

How common is DOK7 p.Arg22Lys (c.65G>A) in the general population?

DOK7 p.Arg22Lys (c.65G>A) is very rare (popmax 0.00721%, sas) (gnomAD).

What do computational predictors say about DOK7 p.Arg22Lys (c.65G>A)?

AlphaMissense predicts likely pathogenic (score 0.8435) — an in-silico prediction, not a clinical call.

DOK7 p.Arg22Lys

c.65G>A · rs756962738 · VCV1034673

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8435 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00721%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital myasthenic syndrome 10

Computational evidence

Protein change
AlphaMissense	0.8435	likely pathogenic
REVEL	0.422	indeterminate
SaProt	LLR -8.53	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.2	GERP -0.51, phastCons 1
Regional constraint	o/e 1.44	unconstrained · MANE · 30 kb · p 2.5e-31 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00721% South Asian · 6/83,242 alleles

Filtering AF 0.00308% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.000582% 8/1,375,312 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00721%	13,874
Remaining individualsnot grpmax-eligible	0.00168%	59,488
European (non-Finnish)	8.75e-05%	1,142,738

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.Arg22Lys
Coding: c.65G>A
MANE Select: NM_173660
dbSNP: rs756962738
Type: single nucleotide variant
Location: chr4:3463516 (GRCh38)
Gene constraint: LOEUF 1.658 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.61
Residue 22: the ph domain

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: fetal akinesia deformation sequence 1

Similar variants

DOK7 p.Arg22= Likely benign ★ same residue
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

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-arg22lys (accessed [today's date]).

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