Is DOCK2 p.Met450Thr (c.1349T>C) pathogenic?

DOCK2 p.Met450Thr (c.1349T>C) is classified Uncertain significance in DOCK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-17). AlphaMissense: likely pathogenic (0.7316); Rare (popmax 0.148%, mid); Associated with DOCK2 deficiency.

What condition is associated with DOCK2 p.Met450Thr (c.1349T>C)?

DOCK2 p.Met450Thr (c.1349T>C) is associated with DOCK2 deficiency (ClinVar).

How common is DOCK2 p.Met450Thr (c.1349T>C) in the general population?

DOCK2 p.Met450Thr (c.1349T>C) is rare (popmax 0.148%, mid) (gnomAD).

What do computational predictors say about DOCK2 p.Met450Thr (c.1349T>C)?

AlphaMissense predicts likely pathogenic (score 0.7316) — an in-silico prediction, not a clinical call.

DOCK2 p.Met450Thr

Q: How is Combined immunodeficiency due to DOCK2 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1349T>C · rs759775916 · VCV542613

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7316 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DOCK2 deficiency

Computational evidence

Protein change
AlphaMissense	0.7316	likely pathogenic
REVEL	0.207	benign-leaning
SaProt	LLR -9.94	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.94 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.1	GERP 2.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 348 kb · p 3.1e-21 · regional, not allelic
Overall
CADD	23.9	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 0.148% Middle Eastern · 9/6,080 alleles

Filtering AF 0.0772% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0577%

Overall 0.00837% 135/1,613,730 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.148%	676
South Asian	0.0461%	2,169
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,867
European (non-Finnish)	0.00644%	15,524
Remaining individualsnot grpmax-eligible	0.0048%	20,823
African / African-American	0.00267%	37,462

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.Met450Thr
Coding: c.1349T>C
MANE Select: NM_004946
dbSNP: rs759775916
Type: single nucleotide variant
Location: chr5:169702393 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.40 · 6 PDB
Residue 450: the c2 dock-type domain

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

Disease context

DOCK2 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to DOCK2 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

DOCK2 p.Met450fs Pathogenic ★ same residue
DOCK2 c.2267+3G>A Uncertain significance ★★ same condition
DOCK2 c.2704-3C>T Uncertain significance ★★ same condition
DOCK2 c.4467+4A>G Uncertain significance ★★ same condition
DOCK2 p.Ala1393Val Uncertain significance ★★ ⚠ same condition
DOCK2 p.Ala1710Val Uncertain significance ★★ ⚠ same condition
DOCK2 p.Ala1765Val Uncertain significance ★★ ⚠ same condition
DOCK2 p.Ala24Pro 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-met450thr (accessed [today's date]).

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