Is DOK7 p.Ala251Val (c.752C>T) pathogenic?

DOK7 p.Ala251Val (c.752C>T) is classified Uncertain significance in DOK7 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-21). AlphaMissense: likely benign (0.0744); Ultra-rare (popmax 0.0375%, eas); Associated with Inborn genetic diseases.

What condition is associated with DOK7 p.Ala251Val (c.752C>T)?

DOK7 p.Ala251Val (c.752C>T) is associated with Inborn genetic diseases, congenital myasthenic syndrome 10, fetal akinesia deformation sequence 1 (ClinVar).

How common is DOK7 p.Ala251Val (c.752C>T) in the general population?

DOK7 p.Ala251Val (c.752C>T) is ultra-rare (popmax 0.0375%, eas) (gnomAD).

What do computational predictors say about DOK7 p.Ala251Val (c.752C>T)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

DOK7 p.Ala251Val

c.752C>T · rs376251309 · VCV575311

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0375%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -7.59	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 0.39	GERP -2
Regional constraint	o/e 1.44	unconstrained · MANE · 30 kb · p 2.5e-31 · regional, not allelic
Overall
CADD	9.427	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0375% East Asian · 16/42,712 alleles

Filtering AF 0.0235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0191%

Overall 0.00369% 58/1,572,398 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0375%	2,669
Admixed American	0.0202%	4,954
African / African-American	0.00945%	10,582
South Asian	0.007%	14,279
Remaining individualsnot grpmax-eligible	0.00493%	20,285
European (non-Finnish)	0.00129%	77,248

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.Ala251Val
Coding: c.752C>T
MANE Select: NM_173660
dbSNP: rs376251309
Type: single nucleotide variant
Location: chr4:3489776 (GRCh38)
Gene constraint: LOEUF 1.658 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.61
Residue 251: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myasthenic syndrome 10 fetal akinesia deformation sequence 1

Similar variants

DOK7 p.Ala251= Benign ★★ same residue
DOK7 p.Ala251Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
DOK7 p.Ala251Ser 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

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-ala251val (accessed [today's date]).

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