Is DOK3 p.Ala252Pro (c.754G>C) pathogenic?

DOK3 p.Ala252Pro (c.754G>C) is classified Uncertain significance in DOK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-20). AlphaMissense: likely pathogenic (0.6048); Very rare (popmax 0.00885%, amr).

How common is DOK3 p.Ala252Pro (c.754G>C) in the general population?

DOK3 p.Ala252Pro (c.754G>C) is very rare (popmax 0.00885%, amr) (gnomAD).

What do computational predictors say about DOK3 p.Ala252Pro (c.754G>C)?

AlphaMissense predicts likely pathogenic (score 0.6048) — an in-silico prediction, not a clinical call.

DOK3 p.Ala252Pro

c.754G>C · VCV3842060

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6048 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00885%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6048	likely pathogenic
REVEL	0.435	indeterminate
SaProt	LLR -10.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.63	GERP -3.2
Regional constraint	o/e 1.01	unconstrained · MANE · 5,554 bp · p 0.73 · regional, not allelic
Overall
CADD	12.89	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A308P vs ClinVar A252P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00885% Admixed American · 5/56,480 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00218%

Overall 0.000314% 5/1,592,718 alleles · very rare

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.Ala252Pro
Coding: c.754G>C
MANE Select: NM_001308236
Type: single nucleotide variant
Location: chr5:177504552 (GRCh38)
Gene constraint: LOEUF 1.47 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.94
Residue 252: the irs-type ptb domain

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

Similar variants

DOK3 p.Ala252Asp Uncertain significance ★ ⚠ same residue
DOK3 p.Ala252Thr Likely benign ★ same residue
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

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-ala252pro (accessed [today's date]).

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