Is DOK7 p.Pro415Ser (c.1243C>T) pathogenic?

DOK7 p.Pro415Ser (c.1243C>T) is classified Benign/Likely benign in DOK7 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-03-27). AlphaMissense: likely benign (0.0703); Common (popmax 11.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with fetal akinesia deformation sequence 1.

What condition is associated with DOK7 p.Pro415Ser (c.1243C>T)?

DOK7 p.Pro415Ser (c.1243C>T) is associated with fetal akinesia deformation sequence 1, congenital myasthenic syndrome 10 (ClinVar).

What do computational predictors say about DOK7 p.Pro415Ser (c.1243C>T)?

AlphaMissense predicts likely benign (score 0.0703) — an in-silico prediction, not a clinical call.

DOK7 p.Pro415Ser

Q: How common is DOK7 p.Pro415Ser (c.1243C>T) in the general population?

DOK7 p.Pro415Ser (c.1243C>T) is common (popmax 11.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1243C>T · rs16844464 · VCV128908

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0703 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 11.8%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

fetal akinesia deformation sequence 1

Computational evidence

Protein change
AlphaMissense	0.0703	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -6.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.46	GERP -0.11, phastCons 0.02
Regional constraint	o/e 1.44	unconstrained · MANE · 30 kb · p 2.5e-31 · regional, not allelic
Overall
CADD	14.93	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 11.8% African / African-American · 8,883/75,010 alleles

Filtering AF 11.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.6%

Overall 4.14% 66,798/1,611,910 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	11.8%	8
Admixed American	9.46%	11
Amishnot grpmax-eligible	8.11%	12
Middle Eastern	7.13%	14
South Asian	6.16%	16
Remaining individualsnot grpmax-eligible	4.58%	22
European (non-Finnish)	3.4%	29
Ashkenazi Jewishnot grpmax-eligible	3.02%	33
East Asian	2.72%	37
Finnishnot grpmax-eligible	1.66%	60

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.Pro415Ser
Coding: c.1243C>T
MANE Select: NM_173660
dbSNP: rs16844464
Type: single nucleotide variant
Location: chr4:3493229 (GRCh38)
Gene constraint: LOEUF 1.658 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.61
Residue 415: a UniProt-annotated variant site (in); the 'disordered' region

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.Pro415Arg Uncertain significance ★★ ⚠ same residue
DOK7 p.Pro415Leu Uncertain significance ★ ⚠ same residue
DOK7 p.Pro415fs 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.Arg158Gln 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-pro415ser (accessed [today's date]).

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