Is DOCK2 p.Val466Met (c.1396G>A) pathogenic?

DOCK2 p.Val466Met (c.1396G>A) is classified Uncertain significance in DOCK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-07). AlphaMissense: likely benign (0.0943); Ultra-rare (popmax 0.0267%, afr); Associated with DOCK2 deficiency.

What condition is associated with DOCK2 p.Val466Met (c.1396G>A)?

DOCK2 p.Val466Met (c.1396G>A) is associated with DOCK2 deficiency (ClinVar).

How common is DOCK2 p.Val466Met (c.1396G>A) in the general population?

DOCK2 p.Val466Met (c.1396G>A) is ultra-rare (popmax 0.0267%, afr) (gnomAD).

What do computational predictors say about DOCK2 p.Val466Met (c.1396G>A)?

AlphaMissense predicts likely benign (score 0.0943) — an in-silico prediction, not a clinical call.

DOCK2 p.Val466Met

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.1396G>A · rs200560235 · VCV937401

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0943 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DOCK2 deficiency

Computational evidence

Protein change
AlphaMissense	0.0943	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -5.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4	GERP 0.3, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 348 kb · p 3.1e-21 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% African / African-American · 20/75,038 alleles

Filtering AF 0.0176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.012% 194/1,613,882 alleles · ultra-rare exomes 167/1,461,564 · genomes 27/152,318 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0672%	1,489
Remaining individualsnot grpmax-eligible	0.0336%	2,976
African / African-Americangrpmax	0.0267%	3,752
East Asian	0.0223%	4,484
European (non-Finnish)	0.00822%	12,164
Admixed American	0.00333%	30,000
South Asian	0.0011%	91,002

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val466Met
Coding: c.1396G>A
MANE Select: NM_004946
dbSNP: rs200560235
Type: single nucleotide variant
Location: chr5:169708181 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.40 · 6 PDB
Residue 466: 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.Val466= Likely benign ★ 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-val466met (accessed [today's date]).

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