Is DOCK8 p.Tyr491fs (c.1470del) pathogenic?

DOCK8 p.Tyr491fs (c.1470del) is classified Pathogenic in DOCK8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-20). Very rare (popmax 0.000254%, nfe); Associated with DOCK8-related disorders.

What condition is associated with DOCK8 p.Tyr491fs (c.1470del)?

DOCK8 p.Tyr491fs (c.1470del) is associated with DOCK8-related disorders, combined immunodeficiency due to DOCK8 deficiency (ClinVar).

How common is DOCK8 p.Tyr491fs (c.1470del) in the general population?

DOCK8 p.Tyr491fs (c.1470del) is very rare (popmax 0.000254%, nfe) (gnomAD).

DOCK8 p.Tyr491fs

c.1470del · rs867378400 · VCV2136718

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

DOCK8-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 13 of 48
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,030 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,048 alleles · very rare

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.Tyr491fs
Coding: c.1470del
MANE Select: NM_203447
dbSNP: rs867378400
Type: Deletion
Location: chr9:339053 (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

DOCK8-related disorders

Also linked: combined immunodeficiency due to DOCK8 deficiency

Similar variants

DOCK8 p.Ala11fs Pathogenic/Likely pathogenic ★★ same condition
DOCK8 p.Leu1754fs Pathogenic ★★ same condition
DOCK8 p.Phe1113fs Pathogenic/Likely 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.404+16del 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-p-tyr491fs (accessed [today's date]).

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