Is DOCK8 p.Arg1008Gln (c.3023G>A) pathogenic?

DOCK8 p.Arg1008Gln (c.3023G>A) is classified Conflicting classifications of pathogenicity in DOCK8 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2025-10-17). AlphaMissense: ambiguous (0.4024); Rare (popmax 0.114%, nfe); Associated with hyper-IgE recurrent infection syndrome 3, autosomal recessive.

How common is DOCK8 p.Arg1008Gln (c.3023G>A) in the general population?

DOCK8 p.Arg1008Gln (c.3023G>A) is rare (popmax 0.114%, nfe) (gnomAD).

What do computational predictors say about DOCK8 p.Arg1008Gln (c.3023G>A)?

AlphaMissense predicts ambiguous (score 0.4024) — an in-silico prediction, not a clinical call.

DOCK8 p.Arg1008Gln

Q: What condition is associated with DOCK8 p.Arg1008Gln (c.3023G>A)?

DOCK8 p.Arg1008Gln (c.3023G>A) is associated with hyper-IgE recurrent infection syndrome 3, autosomal recessive, combined immunodeficiency due to DOCK8 deficiency (ClinVar).

Q: How is Autosomal recessive hyper-IgE syndrome due to ZNF341 deficiency inherited?

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

c.3023G>A · rs145844320 · VCV449248

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

ambiguous

0.4024 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.114%, nfe)

Conditions

hyper-IgE recurrent infection syndrome 3, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.4024	ambiguous
REVEL	0.475	indeterminate
SaProt	LLR -9.28	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.7, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.114% European (non-Finnish) · 1,345/1,180,020 alleles

Filtering AF 0.109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.107%

Overall 0.0932% 1,504/1,614,076 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.114%	877
Remaining individualsnot grpmax-eligible	0.0864%	1,158
Admixed American	0.0617%	1,622
Finnishnot grpmax-eligible	0.0375%	2,667
South Asian	0.0329%	3,036
African / African-American	0.016%	6,249
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804

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.Arg1008Gln
Coding: c.3023G>A
MANE Select: NM_203447
dbSNP: rs145844320
Type: single nucleotide variant
Location: chr9:396837 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.17
Residue 1008: a UniProt-annotated variant site (in)

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

Disease context

hyper-IgE recurrent infection syndrome 3, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined immunodeficiency due to DOCK8 deficiency

For Autosomal recessive hyper-IgE syndrome due to ZNF341 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

DOCK8 p.Arg1008Trp Benign/Likely benign ★★ ⚠ same residue
DOCK8 p.Arg1008= Likely benign ★ same residue
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

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-arg1008gln (accessed [today's date]).

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