Is DOCK8 p.Arg1154Cys (c.3460C>T) pathogenic?

DOCK8 p.Arg1154Cys (c.3460C>T) is classified Conflicting classifications of pathogenicity in DOCK8 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.2159); Rare (popmax 0.825%, mid); Associated with combined immunodeficiency due to DOCK8 deficiency.

What condition is associated with DOCK8 p.Arg1154Cys (c.3460C>T)?

DOCK8 p.Arg1154Cys (c.3460C>T) is associated with combined immunodeficiency due to DOCK8 deficiency (ClinVar).

How common is DOCK8 p.Arg1154Cys (c.3460C>T) in the general population?

DOCK8 p.Arg1154Cys (c.3460C>T) is rare (popmax 0.825%, mid) (gnomAD).

What do computational predictors say about DOCK8 p.Arg1154Cys (c.3460C>T)?

AlphaMissense predicts likely benign (score 0.2159) — an in-silico prediction, not a clinical call.

DOCK8 p.Arg1154Cys

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.3460C>T · rs34390308 · VCV418766

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.2159 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.825%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined immunodeficiency due to DOCK8 deficiency

Computational evidence

Protein change
AlphaMissense	0.2159	likely benign
REVEL	0.288	benign-leaning
SaProt	LLR -9.71	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 5.9	GERP 2.9, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	31.0	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 0.825% Middle Eastern · 50/6,062 alleles

Filtering AF 0.643% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.625%

Overall 0.186% 3,010/1,614,128 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.48%	40
Middle Easterngrpmax	0.825%	121
South Asian	0.687%	145
Remaining individualsnot grpmax-eligible	0.293%	342
Admixed American	0.197%	509
Finnishnot grpmax-eligible	0.105%	955
European (non-Finnish)	0.103%	970
African / African-American	0.0173%	5,772
East Asian	0.00223%	44,880

Ashkenazi Jewish 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
Protein: p.Arg1154Cys
Coding: c.3460C>T
MANE Select: NM_203447
dbSNP: rs34390308
Type: single nucleotide variant
Location: chr9:406999 (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.Arg1154His Uncertain significance ★ ⚠ same residue
DOCK8 p.Arg1154= Likely benign ★ same residue
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

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-arg1154cys (accessed [today's date]).

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