Is DOCK2 p.Leu1065= (c.3195A>C) pathogenic?

DOCK2 p.Leu1065= (c.3195A>C) is classified Benign in DOCK2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 36.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with DOCK2 deficiency.

What condition is associated with DOCK2 p.Leu1065= (c.3195A>C)?

DOCK2 p.Leu1065= (c.3195A>C) is associated with DOCK2 deficiency (ClinVar).

DOCK2 p.Leu1065=

Q: How common is DOCK2 p.Leu1065= (c.3195A>C) in the general population?

DOCK2 p.Leu1065= (c.3195A>C) is common (popmax 36.5%, 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.3195A>C · rs2287727 · VCV1169059

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 36.5%, 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 -0.044	GERP -3.5, phastCons 0.05
Overall
CADD	4.31	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 36.5% East Asian · 16,378/44,842 alleles

Filtering AF 36.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 35.9%

Overall 28.8% 464,239/1,613,724 alleles · common exomes 427,703/1,461,706 · genomes 36,536/152,018 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	36.5%	3
Finnishnot grpmax-eligible	36.2%	3
Amishnot grpmax-eligible	35.1%	3
Ashkenazi Jewishnot grpmax-eligible	34.3%	3
Admixed American	33%	3
South Asian	30%	3
European (non-Finnish)	29.1%	3
Remaining individualsnot grpmax-eligible	28.4%	4
Middle Eastern	19.2%	5
African / African-American	6.35%	16

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.Leu1065=
Coding: c.3195A>C
MANE Select: NM_004946
dbSNP: rs2287727
Type: single nucleotide variant
Location: chr5:170008709 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.40 · 6 PDB
Residue 1065: the 'interaction with crkl' region

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-leu1065 (accessed [today's date]).

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