Is DOK2 p.Pro255Leu (c.764C>T) pathogenic?

DOK2 p.Pro255Leu (c.764C>T) is classified Uncertain significance in DOK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-17). AlphaMissense: likely benign (0.0653); Ultra-rare (popmax 0.0143%, sas).

How common is DOK2 p.Pro255Leu (c.764C>T) in the general population?

DOK2 p.Pro255Leu (c.764C>T) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about DOK2 p.Pro255Leu (c.764C>T)?

AlphaMissense predicts likely benign (score 0.0653) — an in-silico prediction, not a clinical call.

DOK2 p.Pro255Leu

c.764C>T · rs144359058 · VCV2457422

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0653 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0653	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -8.53	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 1.3	GERP -1.7, phastCons 0.011
Regional constraint	o/e 1.22	unconstrained · MANE · 4,287 bp · p 1.6e-07 · regional, not allelic
Overall
CADD	13.8	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 0.0143% South Asian · 13/91,094 alleles

Filtering AF 0.00844% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.00415% 67/1,613,872 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	7,007
European (non-Finnish)	0.00424%	23,601
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
East Asian	0.00223%	44,888
Admixed American	0.00167%	60,000
African / African-American	0.00133%	74,926

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: DOK2
Protein: p.Pro255Leu
Coding: c.764C>T
MANE Select: NM_003974
dbSNP: rs144359058
Type: single nucleotide variant
Location: chr8:21909786 (GRCh38)
Gene constraint: LOEUF 1.838 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.72 · 2 PDB
Residue 255: the 'disordered' region

Full DOK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOK2 p.Ser394Ala Benign ★★ same type
DOK2 p.Ala113Thr Uncertain significance ★ ⚠ same type
DOK2 p.Ala160Thr Uncertain significance ★ same type
DOK2 p.Ala237Val Uncertain significance ★ ⚠ same type
DOK2 p.Ala28Pro Uncertain significance ★ ⚠ same type
DOK2 p.Ala372Val Uncertain significance ★ ⚠ same type
DOK2 p.Ala379Val Uncertain significance ★ ⚠ same type
DOK2 p.Ala37Ser 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/dok2-p-pro255leu (accessed [today's date]).

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