Is DOCK8 p.Pro97Thr (c.289C>A) pathogenic?

DOCK8 p.Pro97Thr (c.289C>A) is classified Benign/Likely benign in DOCK8 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0938); Common (popmax 74.2%, eas) — too common for a highly-penetrant pathogenic allele; Associated with combined immunodeficiency due to DOCK8 deficiency.

What condition is associated with DOCK8 p.Pro97Thr (c.289C>A)?

DOCK8 p.Pro97Thr (c.289C>A) is associated with combined immunodeficiency due to DOCK8 deficiency (ClinVar).

What do computational predictors say about DOCK8 p.Pro97Thr (c.289C>A)?

AlphaMissense predicts likely benign (score 0.0938) — an in-silico prediction, not a clinical call.

DOCK8 p.Pro97Thr

Q: How common is DOCK8 p.Pro97Thr (c.289C>A) in the general population?

DOCK8 p.Pro97Thr (c.289C>A) is common (popmax 74.2%, 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.289C>A · rs529208 · VCV178766

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.0938 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 74.2%, 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	0.0938	likely benign
REVEL	0.201	benign-leaning
SaProt	LLR -7.28	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 4	GERP 1.5, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	22.7	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 74.2% East Asian · 33,284/44,844 alleles

Filtering AF 73.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 73.3%

Overall 50% 806,303/1,613,234 alleles · common exomes 732,667/1,461,370 · genomes 73,636/151,864 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	74.2%	1
Finnishnot grpmax-eligible	56.4%	2
Middle Eastern	54.7%	2
South Asian	54.6%	2
Admixed American	53.5%	2
Remaining individualsnot grpmax-eligible	50.8%	2
European (non-Finnish)	48.8%	2
Ashkenazi Jewishnot grpmax-eligible	47%	2
African / African-American	40.3%	2
Amishnot grpmax-eligible	26%	4

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.Pro97Thr
Coding: c.289C>A
MANE Select: NM_203447
dbSNP: rs529208
Type: single nucleotide variant
Location: chr9:286593 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.17
Residue 97: a UniProt-annotated variant site (in)

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.Pro97Ala Uncertain significance ★ ⚠ 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-pro97thr (accessed [today's date]).

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