Is DOCK8 p.Val759Met (c.2275G>A) pathogenic?

DOCK8 p.Val759Met (c.2275G>A) is classified Conflicting classifications of pathogenicity in DOCK8 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-02-16). AlphaMissense: likely benign (0.1789); Ultra-rare (popmax 0.0823%, mid); Associated with combined immunodeficiency due to DOCK8 deficiency.

What condition is associated with DOCK8 p.Val759Met (c.2275G>A)?

DOCK8 p.Val759Met (c.2275G>A) is associated with combined immunodeficiency due to DOCK8 deficiency, intellectual disability (ClinVar).

How common is DOCK8 p.Val759Met (c.2275G>A) in the general population?

DOCK8 p.Val759Met (c.2275G>A) is ultra-rare (popmax 0.0823%, mid) (gnomAD).

What do computational predictors say about DOCK8 p.Val759Met (c.2275G>A)?

AlphaMissense predicts likely benign (score 0.1789) — an in-silico prediction, not a clinical call.

DOCK8 p.Val759Met

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.2275G>A · rs148693111 · VCV366864

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1789 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0823%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined immunodeficiency due to DOCK8 deficiency

Computational evidence

Protein change
AlphaMissense	0.1789	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -10.67	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.56, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	23.8	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 0.0823% Middle Eastern · 5/6,076 alleles

Filtering AF 0.0437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0394%

Overall 0.0272% 439/1,613,718 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0823%	1,215
South Asian	0.056%	1,786
Remaining individualsnot grpmax-eligible	0.0448%	2,232
European (non-Finnish)	0.0291%	3,440
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,802
Finnishnot grpmax-eligible	0.00628%	15,934
Admixed American	0.005%	20,001
African / African-American	0.004%	24,971

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.Val759Met
Coding: c.2275G>A
MANE Select: NM_203447
dbSNP: rs148693111
Type: single nucleotide variant
Location: chr9:377046 (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

Also linked: intellectual disability

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-val759met (accessed [today's date]).

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