Is DOCK8 p.Ala22Val (c.65C>T) pathogenic?

DOCK8 p.Ala22Val (c.65C>T) is classified Benign/Likely benign in DOCK8 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.2962); Common (popmax 37.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with combined immunodeficiency due to DOCK8 deficiency.

What condition is associated with DOCK8 p.Ala22Val (c.65C>T)?

DOCK8 p.Ala22Val (c.65C>T) is associated with combined immunodeficiency due to DOCK8 deficiency (ClinVar).

What do computational predictors say about DOCK8 p.Ala22Val (c.65C>T)?

AlphaMissense predicts likely benign (score 0.2962) — an in-silico prediction, not a clinical call.

DOCK8 p.Ala22Val

Q: How common is DOCK8 p.Ala22Val (c.65C>T) in the general population?

DOCK8 p.Ala22Val (c.65C>T) is common (popmax 37.5%, eas) — 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.

c.65C>T · rs506121 · VCV137155

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.2962 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 37.5%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined immunodeficiency due to DOCK8 deficiency

Computational evidence

Protein change
AlphaMissense	0.2962	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP -1.2, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	22.0	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 37.5% East Asian · 15,295/40,786 alleles

Filtering AF 37% ClinGen BA1/BS1 input FAF95, joint · FAF99 36.8%

Overall 34.1% 525,872/1,540,820 alleles · common exomes 476,604/1,388,802 · genomes 49,268/152,018 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	39.8%	3
East Asiangrpmax	37.5%	3
European (non-Finnish)	35%	3
Amishnot grpmax-eligible	33.1%	3
Remaining individualsnot grpmax-eligible	33%	3
South Asian	29.2%	3
Middle Eastern	28.7%	3
African / African-American	27.8%	4
Admixed American	27.7%	4
Ashkenazi Jewishnot grpmax-eligible	26.2%	4

Finnish 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.Ala22Val
Coding: c.65C>T
MANE Select: NM_203447
dbSNP: rs506121
Type: single nucleotide variant
Location: chr9:271638 (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.Ala22= 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
DOCK8 p.Arg1388Ter 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-ala22val (accessed [today's date]).

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