Is DOK7 p.Arg158Trp (c.472C>T) pathogenic?

DOK7 p.Arg158Trp (c.472C>T) is classified Conflicting classifications of pathogenicity in DOK7 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-03). AlphaMissense: likely pathogenic (0.8023); Ultra-rare (popmax 0.0164%, mid); Associated with fetal akinesia deformation sequence 1.

What condition is associated with DOK7 p.Arg158Trp (c.472C>T)?

DOK7 p.Arg158Trp (c.472C>T) is associated with fetal akinesia deformation sequence 1, congenital myasthenic syndrome 10 (ClinVar).

How common is DOK7 p.Arg158Trp (c.472C>T) in the general population?

DOK7 p.Arg158Trp (c.472C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about DOK7 p.Arg158Trp (c.472C>T)?

AlphaMissense predicts likely pathogenic (score 0.8023) — an in-silico prediction, not a clinical call.

DOK7 p.Arg158Trp

c.472C>T · rs753436594 · VCV643080

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8023 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

fetal akinesia deformation sequence 1

Computational evidence

Protein change
AlphaMissense	0.8023	likely pathogenic
REVEL	0.751	pathogenic-leaning
SaProt	LLR -14.67	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.12, phastCons 1
Regional constraint	o/e 1.44	unconstrained · MANE · 30 kb · p 2.5e-31 · regional, not allelic
Overall
CADD	34.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000806% 13/1,613,750 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.0022%	45,537
Admixed American	0.00167%	60,002
Finnishnot grpmax-eligible	0.00157%	63,758
African / African-American	0.00134%	74,898
European (non-Finnish)	0.000593%	168,576

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.Arg158Trp
Coding: c.472C>T
MANE Select: NM_173660
dbSNP: rs753436594
Type: single nucleotide variant
Location: chr4:3476482 (GRCh38)
Gene constraint: LOEUF 1.658 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.61
Residue 158: the irs-type ptb domain; a UniProt-annotated variant site (in cms10; results in a significant reduction of achr clusters)

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 p.Arg158Gln Pathogenic/Likely pathogenic ★★ 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.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-arg158trp (accessed [today's date]).

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