Is DOCK8 p.Leu452= (c.1356G>A) pathogenic?

DOCK8 p.Leu452= (c.1356G>A) is classified Benign/Likely benign in DOCK8 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-04-01). Rare (popmax 0.947%, afr); Associated with combined immunodeficiency due to DOCK8 deficiency.

What condition is associated with DOCK8 p.Leu452= (c.1356G>A)?

DOCK8 p.Leu452= (c.1356G>A) is associated with combined immunodeficiency due to DOCK8 deficiency (ClinVar).

How common is DOCK8 p.Leu452= (c.1356G>A) in the general population?

DOCK8 p.Leu452= (c.1356G>A) is rare (popmax 0.947%, afr) (gnomAD).

DOCK8 p.Leu452=

Q: How is Combined immunodeficiency due to DOCK8 deficiency inherited?

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

c.1356G>A · rs113175936 · VCV377795

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.947%, afr)

Conditions

combined immunodeficiency due to DOCK8 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 2.4	GERP -3.8, phastCons 1
Overall
CADD	6.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.947% African / African-American · 711/75,040 alleles

Filtering AF 0.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.867%

Overall 0.0496% 801/1,614,166 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.947%	106
Remaining individualsnot grpmax-eligible	0.0736%	1,359
Admixed American	0.0533%	1,876
Middle Eastern	0.0495%	2,021
South Asian	0.0022%	45,543
European (non-Finnish)	0.000593%	168,574

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: DOCK8
Protein: p.Leu452=
Coding: c.1356G>A
MANE Select: NM_203447
dbSNP: rs113175936
Type: single nucleotide variant
Location: chr9:336652 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.17

Full DOCK8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined immunodeficiency due to DOCK8 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to DOCK8 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

DOCK8 c.1680-2A>G Likely pathogenic ★★ same condition
DOCK8 c.2779-2A>C Likely pathogenic ★★ same condition
DOCK8 c.2971-1G>A Pathogenic ★★ same condition
DOCK8 c.3530+1G>A Likely pathogenic ★★ same condition
DOCK8 c.528+1G>A Likely pathogenic ★★ same condition
DOCK8 c.529-2A>G Likely pathogenic ★★ same condition
DOCK8 p.Arg1388Ter Pathogenic ★★ same condition
DOCK8 p.Arg1796Ter Pathogenic ★★ 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/dock8-p-leu452 (accessed [today's date]).

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