Is DOK3 p.Ser219Phe (c.656C>T) pathogenic?

DOK3 p.Ser219Phe (c.656C>T) is classified Uncertain significance in DOK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely pathogenic (0.6628); Ultra-rare (popmax 0.0167%, amr).

How common is DOK3 p.Ser219Phe (c.656C>T) in the general population?

DOK3 p.Ser219Phe (c.656C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about DOK3 p.Ser219Phe (c.656C>T)?

AlphaMissense predicts likely pathogenic (score 0.6628) — an in-silico prediction, not a clinical call.

DOK3 p.Ser219Phe

c.656C>T · rs367771899 · VCV2514163

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6628 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6628	likely pathogenic
REVEL	0.739	pathogenic-leaning
SaProt	LLR -9.34	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 5,554 bp · p 0.73 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S275F vs ClinVar S219F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Admixed American · 10/59,992 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00391% 63/1,612,976 alleles · ultra-rare exomes 56/1,460,744 · genomes 7/152,232 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,999
European (non-Finnish)	0.00407%	24,580
African / African-American	0.004%	24,979
Remaining individualsnot grpmax-eligible	0.0032%	31,221

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: DOK3
Protein: p.Ser219Phe
Coding: c.656C>T
MANE Select: NM_001308236
dbSNP: rs367771899
Type: single nucleotide variant
Location: chr5:177504650 (GRCh38)
Gene constraint: LOEUF 1.47 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.94
Residue 275 UniProt numbering: the irs-type ptb domain

Full DOK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DOK3 c.-102G>T Uncertain significance ★ ⚠ same type
DOK3 c.-181C>T Uncertain significance ★ ⚠ same type
DOK3 c.-182G>A Uncertain significance ★ ⚠ same type
DOK3 c.-182G>C Uncertain significance ★ ⚠ same type
DOK3 c.-23C>T Uncertain significance ★ ⚠ same type
DOK3 c.-35G>A Uncertain significance ★ ⚠ same type
DOK3 c.-62C>T Uncertain significance ★ ⚠ same type
DOK3 c.-69G>A 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/dok3-p-ser219phe (accessed [today's date]).

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