Is DOK7 p.Pro421His (c.1262C>A) pathogenic?

DOK7 p.Pro421His (c.1262C>A) is classified Uncertain significance in DOK7 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-07-05). AlphaMissense: likely benign (0.0794); Ultra-rare (popmax 0.0133%, amr); Associated with Inborn genetic diseases.

What condition is associated with DOK7 p.Pro421His (c.1262C>A)?

DOK7 p.Pro421His (c.1262C>A) is associated with Inborn genetic diseases, congenital myasthenic syndrome 10, fetal akinesia deformation sequence 1 (ClinVar).

How common is DOK7 p.Pro421His (c.1262C>A) in the general population?

DOK7 p.Pro421His (c.1262C>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about DOK7 p.Pro421His (c.1262C>A)?

AlphaMissense predicts likely benign (score 0.0794) — an in-silico prediction, not a clinical call.

DOK7 p.Pro421His

c.1262C>A · rs373261147 · VCV465671

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0794 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0794	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -7.43	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 2.3	GERP 0.98, phastCons 0.015
Regional constraint	o/e 1.44	unconstrained · MANE · 30 kb · p 2.5e-31 · regional, not allelic
Overall
CADD	16.82	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 0.0133% Admixed American · 8/59,976 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00546% 88/1,611,954 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,497
Remaining individualsnot grpmax-eligible	0.00801%	12,484
European (non-Finnish)	0.00619%	16,160
African / African-American	0.00133%	75,050
South Asian	0.0011%	91,006

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.Pro421His
Coding: c.1262C>A
MANE Select: NM_173660
dbSNP: rs373261147
Type: single nucleotide variant
Location: chr4:3493248 (GRCh38)
Gene constraint: LOEUF 1.658 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.61
Residue 421: 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.Pro421Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
DOK7 p.Pro421Leu Uncertain significance ★ ⚠ same residue
DOK7 p.Pro421= Likely benign ★ same residue
DOK7 p.Pro421Ala Uncertain significance ★ ⚠ 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

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-pro421his (accessed [today's date]).

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