Is DOCK8 p.Asn561Lys (c.1683C>A) pathogenic?

DOCK8 p.Asn561Lys (c.1683C>A) is classified Uncertain significance in DOCK8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-13). AlphaMissense: likely pathogenic (0.9832); Ultra-rare (popmax 0.0382%, nfe); Associated with combined immunodeficiency due to DOCK8 deficiency.

What condition is associated with DOCK8 p.Asn561Lys (c.1683C>A)?

DOCK8 p.Asn561Lys (c.1683C>A) is associated with combined immunodeficiency due to DOCK8 deficiency (ClinVar).

How common is DOCK8 p.Asn561Lys (c.1683C>A) in the general population?

DOCK8 p.Asn561Lys (c.1683C>A) is ultra-rare (popmax 0.0382%, nfe) (gnomAD).

What do computational predictors say about DOCK8 p.Asn561Lys (c.1683C>A)?

AlphaMissense predicts likely pathogenic (score 0.9832) — an in-silico prediction, not a clinical call.

DOCK8 p.Asn561Lys

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.1683C>A · rs372278912 · VCV912503

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9832 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0382%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

combined immunodeficiency due to DOCK8 deficiency

Computational evidence

Protein change
AlphaMissense	0.9832	likely pathogenic · top 2% in DOCK8
REVEL	0.425	indeterminate
SaProt	LLR -13.94	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.1	GERP -4.1, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0382% European (non-Finnish) · 450/1,178,094 alleles

Filtering AF 0.0352% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0341%

Overall 0.0285% 460/1,611,876 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0382%	2,618
Remaining individualsnot grpmax-eligible	0.00801%	12,485
African / African-American	0.00535%	18,704
Admixed American	0.00167%	59,998

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.Asn561Lys
Coding: c.1683C>A
MANE Select: NM_203447
dbSNP: rs372278912
Type: single nucleotide variant
Location: chr9:368021 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.17
Residue 561: the c2 dock-type domain

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-asn561lys (accessed [today's date]).

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