Is DOCK8 p.Lys473Arg (c.1418A>G) pathogenic?

DOCK8 p.Lys473Arg (c.1418A>G) is classified Pathogenic in DOCK8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-27). AlphaMissense: likely benign (0.1009); Absent from gnomAD v4.1; Associated with combined immunodeficiency due to DOCK8 deficiency.

How common is DOCK8 p.Lys473Arg (c.1418A>G) in the general population?

DOCK8 p.Lys473Arg (c.1418A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DOCK8 p.Lys473Arg (c.1418A>G)?

AlphaMissense predicts likely benign (score 0.1009) — an in-silico prediction, not a clinical call.

DOCK8 p.Lys473Arg

Q: What condition is associated with DOCK8 p.Lys473Arg (c.1418A>G)?

DOCK8 p.Lys473Arg (c.1418A>G) is associated with combined immunodeficiency due to DOCK8 deficiency, severe combined immunodeficiency (ClinVar).

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.1418A>G · rs112321280 · VCV949

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1009 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined immunodeficiency due to DOCK8 deficiency

Computational evidence

Protein change
AlphaMissense	0.1009	likely benign ⚠ discordant with ClinVar
REVEL	0.256	benign-leaning
SaProt	LLR -5.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.54	donor gain · deltas
Pangolin	Δ0.67	gain · loss 0.61 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 2.2, 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DOCK8
Protein: p.Lys473Arg
Coding: c.1418A>G
MANE Select: NM_203447
dbSNP: rs112321280
Type: single nucleotide variant
Location: chr9:336714 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.17
Residue 473: a UniProt-annotated variant site (in hies2)

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

Also linked: severe combined immunodeficiency

For Combined immunodeficiency due to DOCK8 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

DOCK8 p.Lys473Asn Uncertain significance ★ ⚠ 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
DOCK8 p.Arg1388Ter 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-lys473arg (accessed [today's date]).

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