Is DOCK2 p.Lys458= (c.1374A>G) pathogenic?

DOCK2 p.Lys458= (c.1374A>G) is classified Benign in DOCK2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 68.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with DOCK2 deficiency.

What condition is associated with DOCK2 p.Lys458= (c.1374A>G)?

DOCK2 p.Lys458= (c.1374A>G) is associated with DOCK2 deficiency (ClinVar).

DOCK2 p.Lys458=

Q: How common is DOCK2 p.Lys458= (c.1374A>G) in the general population?

DOCK2 p.Lys458= (c.1374A>G) is common (popmax 68.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1374A>G · rs2306559 · VCV1169571

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 68.5%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

DOCK2 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.15	GERP -4.2
Overall
CADD	2.047	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 68.5% East Asian · 30,691/44,790 alleles

Filtering AF 67.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 67.6%

Overall 43.1% 695,686/1,613,106 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	68.5%	1
Amishnot grpmax-eligible	49.2%	2
European (non-Finnish)	45.4%	2
Ashkenazi Jewishnot grpmax-eligible	43.3%	2
Remaining individualsnot grpmax-eligible	43%	2
Middle Eastern	41.4%	2
Finnishnot grpmax-eligible	38.3%	3
South Asian	31.9%	3
Admixed American	28.4%	4
African / African-American	22.5%	4

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.Lys458=
Coding: c.1374A>G
MANE Select: NM_004946
dbSNP: rs2306559
Type: single nucleotide variant
Location: chr5:169702418 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.40 · 6 PDB
Residue 458: 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 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
DOCK2 p.Ala454Val 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-lys458 (accessed [today's date]).

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