Is DOCK8 c.404+16del pathogenic?

DOCK8 c.404+16del is classified Benign/Likely benign in DOCK8 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 6.24%, sas) — too common for a highly-penetrant pathogenic allele; Associated with combined immunodeficiency due to DOCK8 deficiency.

What condition is associated with DOCK8 c.404+16del?

DOCK8 c.404+16del is associated with combined immunodeficiency due to DOCK8 deficiency (ClinVar).

DOCK8 c.404+16del

Q: How common is DOCK8 c.404+16del in the general population?

DOCK8 c.404+16del is common (popmax 6.24%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Combined immunodeficiency due to DOCK8 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

rs727505303 · VCV180037

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 6.24%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

combined immunodeficiency due to DOCK8 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +16	near-intronic (+16 nt from the splice site)
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.2	GERP -5.3
Non-coding constraint	Z -0.23	1 kb window · o/e 1.02 · regional · uncalibrated
Overall
CADD	5.256	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.24% South Asian · 5,584/89,526 alleles

Filtering AF 6.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.04%

Overall 3.22% 51,831/1,607,164 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	13.8%	7
Ashkenazi Jewishnot grpmax-eligible	6.27%	16
South Asiangrpmax	6.24%	16
Middle Eastern	4.05%	25
European (non-Finnish)	3.22%	31
Remaining individualsnot grpmax-eligible	3.02%	33
African / African-American	2.84%	35
Admixed American	1.81%	55
Finnishnot grpmax-eligible	1.63%	61
East Asian	0.0268%	3,728

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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
Coding: c.404+16del
MANE Select: NM_203447
dbSNP: rs727505303
Type: Deletion
Location: chr9:289591 (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 p.Leu1754fs Pathogenic ★★ same condition
DOCK8 p.Phe1113fs Pathogenic/Likely pathogenic ★★ same condition
DOCK8 p.Tyr491fs Pathogenic ★★ same condition
DOCK8 c.2109+11del Benign/Likely benign ★★ same condition
DOCK8 c.3234+15del Benign/Likely benign ★★ same condition
DOCK8 c.3234+8del Benign ★★ same condition
DOCK8 c.333-8del Likely benign ★★ same condition
DOCK8 c.53+14del Benign/Likely benign ★★ 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-c-404-plus-16del (accessed [today's date]).

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