Is DOCK8 p.Lys604= (c.1812A>G) pathogenic?

DOCK8 p.Lys604= (c.1812A>G) is classified Benign/Likely benign in DOCK8 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). Common (popmax 27.8%, mid) — too common for a highly-penetrant pathogenic allele; Associated with combined immunodeficiency due to DOCK8 deficiency.

What condition is associated with DOCK8 p.Lys604= (c.1812A>G)?

DOCK8 p.Lys604= (c.1812A>G) is associated with combined immunodeficiency due to DOCK8 deficiency (ClinVar).

DOCK8 p.Lys604=

Q: How common is DOCK8 p.Lys604= (c.1812A>G) in the general population?

DOCK8 p.Lys604= (c.1812A>G) is common (popmax 27.8%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1812A>G · rs913703 · VCV137137

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Common

common (popmax 27.8%, mid) — too common for a highly-penetrant pathogenic allele

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 2.1	GERP -1.9, phastCons 1
Overall
CADD	7.76	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 27.8% Middle Eastern · 1,682/6,050 alleles

Filtering AF 26.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 26.2%

Overall 23.4% 377,492/1,611,044 alleles · common exomes 341,983/1,458,890 · genomes 35,509/152,154 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	32.9%	3
Middle Easterngrpmax	27.8%	4
African / African-American	26.7%	4
South Asian	25.5%	4
European (non-Finnish)	24.2%	4
Remaining individualsnot grpmax-eligible	23.8%	4
Admixed American	20.2%	5
Ashkenazi Jewishnot grpmax-eligible	20.1%	5
Finnishnot grpmax-eligible	18%	6
East Asian	7.84%	13

Amish 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: DOCK8
Protein: p.Lys604=
Coding: c.1812A>G
MANE Select: NM_203447
dbSNP: rs913703
Type: single nucleotide variant
Location: chr9:370244 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.17
Residue 604: the c2 dock-type domain

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-lys604 (accessed [today's date]).

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