Is DOCK8 p.Leu75Val (c.223C>G) pathogenic?

DOCK8 p.Leu75Val (c.223C>G) is classified Uncertain significance in DOCK8 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-07-26). AlphaMissense: likely benign (0.0799); Ultra-rare (popmax 0.0653%, afr); Associated with Inborn genetic diseases.

What condition is associated with DOCK8 p.Leu75Val (c.223C>G)?

DOCK8 p.Leu75Val (c.223C>G) is associated with Inborn genetic diseases, combined immunodeficiency due to DOCK8 deficiency (ClinVar).

How common is DOCK8 p.Leu75Val (c.223C>G) in the general population?

DOCK8 p.Leu75Val (c.223C>G) is ultra-rare (popmax 0.0653%, afr) (gnomAD).

What do computational predictors say about DOCK8 p.Leu75Val (c.223C>G)?

AlphaMissense predicts likely benign (score 0.0799) — an in-silico prediction, not a clinical call.

DOCK8 p.Leu75Val

c.223C>G · rs368133450 · VCV844078

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0799 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0653%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0799	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -6.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.49, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	15.56	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0653% African / African-American · 49/75,024 alleles

Filtering AF 0.0507% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0455%

Overall 0.00347% 56/1,614,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0653%	1,531
Remaining individualsnot grpmax-eligible	0.0064%	15,625
Admixed American	0.005%	20,001

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.Leu75Val
Coding: c.223C>G
MANE Select: NM_203447
dbSNP: rs368133450
Type: single nucleotide variant
Location: chr9:286527 (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 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-leu75val (accessed [today's date]).

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