Is DOK4 p.Arg200Trp (c.598C>T) pathogenic?

DOK4 p.Arg200Trp (c.598C>T) is classified Uncertain significance in DOK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-03). AlphaMissense: likely pathogenic (0.995); Ultra-rare (popmax 0.0167%, mid).

How common is DOK4 p.Arg200Trp (c.598C>T) in the general population?

DOK4 p.Arg200Trp (c.598C>T) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about DOK4 p.Arg200Trp (c.598C>T)?

AlphaMissense predicts likely pathogenic (score 0.995) — an in-silico prediction, not a clinical call.

DOK4 p.Arg200Trp

c.598C>T · rs761102101 · VCV2356151

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.995 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.995	likely pathogenic
REVEL	0.92	moderately pathogenic-leaning
SaProt	LLR -14.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP -4.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 6,127 bp · p 0.03 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0167% Middle Eastern · 1/5,988 alleles

Filtering AF 0.00538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00498%

Overall 0.00558% 90/1,613,388 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,988
African / African-American	0.00667%	14,984
European (non-Finnish)	0.00661%	15,127
South Asian	0.0033%	30,340
Remaining individualsnot grpmax-eligible	0.0032%	31,226
Admixed American	0.00167%	59,960

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: DOK4
Protein: p.Arg200Trp
Coding: c.598C>T
MANE Select: NM_018110
dbSNP: rs761102101
Type: single nucleotide variant
Location: chr16:57474794 (GRCh38)
Gene constraint: LOEUF 0.915 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.73
Residue 200: the irs-type ptb domain

Full DOK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOK4 p.Glu74Asp Benign ★★ same type
DOK4 p.Ala191Thr Uncertain significance ★ ⚠ same type
DOK4 p.Ala204Thr Uncertain significance ★ ⚠ same type
DOK4 p.Ala229Ser Uncertain significance ★ ⚠ same type
DOK4 p.Ala294Gly Uncertain significance ★ ⚠ same type
DOK4 p.Ala294Pro Uncertain significance ★ ⚠ same type
DOK4 p.Arg115Cys Uncertain significance ★ ⚠ same type
DOK4 p.Arg138Cys Uncertain significance ★ ⚠ same type

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/dok4-p-arg200trp (accessed [today's date]).

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