Is DOK7 p.Ser346Phe (c.1037C>T) pathogenic?

DOK7 p.Ser346Phe (c.1037C>T) is classified Uncertain significance in DOK7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-28). AlphaMissense: ambiguous (0.5217); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with DOK7 p.Ser346Phe (c.1037C>T)?

DOK7 p.Ser346Phe (c.1037C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DOK7 p.Ser346Phe (c.1037C>T) in the general population?

DOK7 p.Ser346Phe (c.1037C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about DOK7 p.Ser346Phe (c.1037C>T)?

AlphaMissense predicts ambiguous (score 0.5217) — an in-silico prediction, not a clinical call.

DOK7 p.Ser346Phe

c.1037C>T · rs568530359 · VCV2663666

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5217 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5217	ambiguous
REVEL	0.397	indeterminate
SaProt	LLR -9.83	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP -0.11, phastCons 1
Regional constraint	o/e 1.44	unconstrained · MANE · 30 kb · p 2.5e-31 · regional, not allelic
Overall
CADD	27.4	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 0.0107% African / African-American · 8/74,462 alleles

Filtering AF 0.00531% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00383%

Overall 0.00134% 21/1,569,448 alleles · ultra-rare exomes 16/1,417,106 · genomes 5/152,342 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,308
South Asian	0.00345%	28,975
European (non-Finnish)	0.00086%	116,243

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.Ser346Phe
Coding: c.1037C>T
MANE Select: NM_173660
dbSNP: rs568530359
Type: single nucleotide variant
Location: chr4:3493023 (GRCh38)
Gene constraint: LOEUF 1.658 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.61
Residue 346: 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

Similar variants

DOK7 p.Ser346Cys Uncertain significance ★ ⚠ same residue
DOK7 p.Ser346= Likely benign ★ same residue
DOK7 p.Ala251Val Uncertain significance ★★ ⚠ same condition
DOK7 p.Ala356Val Uncertain significance ★★ ⚠ same condition
DOK7 p.Ala380Val Uncertain significance ★★ ⚠ same condition
DOK7 p.Ala403Gly Uncertain significance ★★ ⚠ same condition
DOK7 p.Ala482Glu Uncertain significance ★★ ⚠ same condition
DOK7 p.Ala482Val Uncertain significance ★★ ⚠ 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-ser346phe (accessed [today's date]).

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