Is DOK7 p.Ser249Ter (c.746C>G) pathogenic?

DOK7 p.Ser249Ter (c.746C>G) is classified Likely pathogenic in DOK7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-14). Very rare (popmax 8.63e-05%, nfe); Associated with fetal akinesia deformation sequence 3.

What condition is associated with DOK7 p.Ser249Ter (c.746C>G)?

DOK7 p.Ser249Ter (c.746C>G) is associated with fetal akinesia deformation sequence 3 (ClinVar).

How common is DOK7 p.Ser249Ter (c.746C>G) in the general population?

DOK7 p.Ser249Ter (c.746C>G) is very rare (popmax 8.63e-05%, nfe) (gnomAD).

DOK7 p.Ser249Ter

c.746C>G · rs1286718786 · VCV2674875

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.63e-05%, nfe)

Conditions

fetal akinesia deformation sequence 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (6 of 7, 26 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 0.99, phastCons 0.63
Overall
CADD	37.0	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 8.63e-05% European (non-Finnish) · 1/1,159,114 alleles

Overall 0.000141% 2/1,421,122 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00164%	60,934
European (non-Finnish)grpmax	8.63e-05%	1,159,114

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser249Ter
Coding: c.746C>G
MANE Select: NM_173660
dbSNP: rs1286718786
Type: single nucleotide variant
Location: chr4:3489770 (GRCh38)
Gene constraint: LOEUF 1.658 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.61
Residue 249: the 'disordered' region

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

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 p.Arg201Ter Pathogenic ★★ same condition
DOK7 p.Cys412Ter Pathogenic ★★ same condition
DOK7 p.Gln151Ter Pathogenic/Likely pathogenic ★★ same condition
DOK7 p.Gln296Ter Likely pathogenic ★★ same condition
DOK7 p.Gln423Ter 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-ser249ter (accessed [today's date]).

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