Is DOK2 p.Phe209Ser (c.626T>C) pathogenic?

DOK2 p.Phe209Ser (c.626T>C) is classified Uncertain significance in DOK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-24). AlphaMissense: likely pathogenic (0.9951); Very rare (popmax 0.0011%, sas).

How common is DOK2 p.Phe209Ser (c.626T>C) in the general population?

DOK2 p.Phe209Ser (c.626T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about DOK2 p.Phe209Ser (c.626T>C)?

AlphaMissense predicts likely pathogenic (score 0.9951) — an in-silico prediction, not a clinical call.

DOK2 p.Phe209Ser

c.626T>C · rs2486346202 · VCV2551653

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9951	likely pathogenic · top 1% in DOK2
REVEL	0.947	strongly pathogenic-leaning
SaProt	LLR -16.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.20	acceptor loss, 15 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 1.22	unconstrained · MANE · 4,287 bp · p 1.6e-07 · regional, not allelic
Overall
CADD	28.8	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 0.0011% South Asian · 1/91,030 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000412% 6/1,456,426 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,030
European (non-Finnish)	0.000424%	235,702

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.Phe209Ser
Coding: c.626T>C
MANE Select: NM_003974
dbSNP: rs2486346202
Type: single nucleotide variant
Location: chr8:21909924 (GRCh38)
Gene constraint: LOEUF 1.838 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.72 · 2 PDB
Residue 209: the irs-type ptb domain; a β-strand

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-phe209ser (accessed [today's date]).

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