Is DOK3 p.Val40Met (c.118G>A) pathogenic?

DOK3 p.Val40Met (c.118G>A) is classified Uncertain significance in DOK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely pathogenic (0.6685); Ultra-rare (popmax 0.0176%, mid).

How common is DOK3 p.Val40Met (c.118G>A) in the general population?

DOK3 p.Val40Met (c.118G>A) is ultra-rare (popmax 0.0176%, mid) (gnomAD).

What do computational predictors say about DOK3 p.Val40Met (c.118G>A)?

AlphaMissense predicts likely pathogenic (score 0.6685) — an in-silico prediction, not a clinical call.

DOK3 p.Val40Met

c.118G>A · rs1375659637 · VCV2525000

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6685 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6685	likely pathogenic
REVEL	0.231	benign-leaning
SaProt	LLR -8.72	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.63, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 5,554 bp · p 0.73 · regional, not allelic
Overall
CADD	25.1	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 V96M vs ClinVar V40M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0176% Middle Eastern · 1/5,680 alleles

Filtering AF 0.00234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0014%

Overall 0.000818% 13/1,589,312 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0176%	5,680
Admixed American	0.00701%	14,259
African / African-American	0.00402%	24,849
Remaining individualsnot grpmax-eligible	0.00163%	61,436
South Asian	0.00114%	87,636
European (non-Finnish)	0.000257%	389,416

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.Val40Met
Coding: c.118G>A
MANE Select: NM_001308236
dbSNP: rs1375659637
Type: single nucleotide variant
Location: chr5:177508491 (GRCh38)
Gene constraint: LOEUF 1.47 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.94

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-val40met (accessed [today's date]).

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