Is DOCK8 p.Glu227Lys (c.679G>A) pathogenic?

DOCK8 p.Glu227Lys (c.679G>A) is classified Benign/Likely benign in DOCK8 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1137); Low-frequency (popmax 1.78%, eas); Associated with combined immunodeficiency due to DOCK8 deficiency.

What condition is associated with DOCK8 p.Glu227Lys (c.679G>A)?

DOCK8 p.Glu227Lys (c.679G>A) is associated with combined immunodeficiency due to DOCK8 deficiency (ClinVar).

How common is DOCK8 p.Glu227Lys (c.679G>A) in the general population?

DOCK8 p.Glu227Lys (c.679G>A) is low-frequency (popmax 1.78%, eas) (gnomAD).

What do computational predictors say about DOCK8 p.Glu227Lys (c.679G>A)?

AlphaMissense predicts likely benign (score 0.1137) — an in-silico prediction, not a clinical call.

DOCK8 p.Glu227Lys

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.679G>A · rs76276364 · VCV516569

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1137 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.78%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined immunodeficiency due to DOCK8 deficiency

Computational evidence

Protein change
AlphaMissense	0.1137	likely benign
REVEL	0.241	benign-leaning
SaProt	LLR -5.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 2.3, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	24.8	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 1.78% East Asian · 797/44,890 alleles

Filtering AF 1.67% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.63%

Overall 0.0619% 999/1,614,224 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.78%	56
Remaining individualsnot grpmax-eligible	0.107%	933
Middle Eastern	0.066%	1,516
South Asian	0.0439%	2,277
Admixed American	0.0316%	3,160
African / African-American	0.0107%	9,382
European (non-Finnish)	0.00534%	18,731
Finnishnot grpmax-eligible	0.00156%	64,040

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.Glu227Lys
Coding: c.679G>A
MANE Select: NM_203447
dbSNP: rs76276364
Type: single nucleotide variant
Location: chr9:312104 (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-glu227lys (accessed [today's date]).

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