Is DOCK8 p.Arg478His (c.1433G>A) pathogenic?

DOCK8 p.Arg478His (c.1433G>A) is classified Uncertain significance in DOCK8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-21). AlphaMissense: ambiguous (0.4125); Very rare (popmax 0.00892%, eas); Associated with Inborn genetic diseases.

What condition is associated with DOCK8 p.Arg478His (c.1433G>A)?

DOCK8 p.Arg478His (c.1433G>A) is associated with Inborn genetic diseases, combined immunodeficiency due to DOCK8 deficiency (ClinVar).

How common is DOCK8 p.Arg478His (c.1433G>A) in the general population?

DOCK8 p.Arg478His (c.1433G>A) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about DOCK8 p.Arg478His (c.1433G>A)?

AlphaMissense predicts ambiguous (score 0.4125) — an in-silico prediction, not a clinical call.

DOCK8 p.Arg478His

c.1433G>A · rs757667271 · VCV1437906

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4125 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4125	ambiguous
REVEL	0.327	indeterminate
SaProt	LLR -10.45	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	32.0	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 0.00892% East Asian · 4/44,850 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000434% 7/1,614,038 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,212
European (non-Finnish)	0.000254%	393,323

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.Arg478His
Coding: c.1433G>A
MANE Select: NM_203447
dbSNP: rs757667271
Type: single nucleotide variant
Location: chr9:339016 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined immunodeficiency due to DOCK8 deficiency

Similar variants

DOCK8 p.Arg478Cys Uncertain significance ★ ⚠ same residue
DOCK8 p.Arg478= 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-arg478his (accessed [today's date]).

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