Is DOCK2 p.Met490Thr (c.1469T>C) pathogenic?

DOCK2 p.Met490Thr (c.1469T>C) is classified Uncertain significance in DOCK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). AlphaMissense: ambiguous (0.4771); Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DOCK2 p.Met490Thr (c.1469T>C)?

DOCK2 p.Met490Thr (c.1469T>C) is associated with Inborn genetic diseases (ClinVar).

How common is DOCK2 p.Met490Thr (c.1469T>C) in the general population?

DOCK2 p.Met490Thr (c.1469T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about DOCK2 p.Met490Thr (c.1469T>C)?

AlphaMissense predicts ambiguous (score 0.4771) — an in-silico prediction, not a clinical call.

DOCK2 p.Met490Thr

c.1469T>C · VCV3504399

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4771 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4771	ambiguous
REVEL	0.139	moderately benign-leaning
SaProt	LLR -9.52	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.1	GERP -0.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 348 kb · p 3.1e-21 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,884 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,406 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: DOCK2
Protein: p.Met490Thr
Coding: c.1469T>C
MANE Select: NM_004946
Type: single nucleotide variant
Location: chr5:169708254 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.40 · 6 PDB
Residue 490: the c2 dock-type domain

Full DOCK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DOCK2 p.Met490Leu Uncertain significance ★ ⚠ same residue
DOCK2 p.Ala1765Val Uncertain significance ★★ ⚠ same condition
DOCK2 p.Ala812Val Uncertain significance ★★ ⚠ same condition
DOCK2 p.Arg1071Cys Uncertain significance ★★ ⚠ same condition
DOCK2 p.Arg11Gln Uncertain significance ★★ ⚠ same condition
DOCK2 p.Arg1200His Uncertain significance ★★ ⚠ same condition
DOCK2 p.Arg1274Gln Uncertain significance ★★ ⚠ same condition
DOCK2 p.Arg1480Cys Uncertain significance ★★ ⚠ same condition

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/dock2-p-met490thr (accessed [today's date]).

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