Is DOCK8 p.Ile673Phe (c.2017A>T) pathogenic?

DOCK8 p.Ile673Phe (c.2017A>T) is classified Conflicting classifications of pathogenicity in DOCK8 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2024-11-11). AlphaMissense: likely benign (0.2396); Ultra-rare (popmax 0.066%, mid); Associated with combined immunodeficiency due to DOCK8 deficiency.

What condition is associated with DOCK8 p.Ile673Phe (c.2017A>T)?

DOCK8 p.Ile673Phe (c.2017A>T) is associated with combined immunodeficiency due to DOCK8 deficiency, hyper-IgE recurrent infection syndrome 3, autosomal recessive (ClinVar).

How common is DOCK8 p.Ile673Phe (c.2017A>T) in the general population?

DOCK8 p.Ile673Phe (c.2017A>T) is ultra-rare (popmax 0.066%, mid) (gnomAD).

What do computational predictors say about DOCK8 p.Ile673Phe (c.2017A>T)?

AlphaMissense predicts likely benign (score 0.2396) — an in-silico prediction, not a clinical call.

DOCK8 p.Ile673Phe

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.2017A>T · rs372858877 · VCV228615

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2396 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined immunodeficiency due to DOCK8 deficiency

Computational evidence

Protein change
AlphaMissense	0.2396	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -9.70	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 3.5	GERP -3.8, phastCons 0.99
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	19.48	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 0.066% Middle Eastern · 4/6,062 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.0113% 182/1,613,978 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,516
European (non-Finnish)	0.0136%	7,375
African / African-American	0.012%	8,338
Remaining individualsnot grpmax-eligible	0.008%	12,500
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Admixed American	0.00333%	30,012
South Asian	0.0011%	91,080

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.Ile673Phe
Coding: c.2017A>T
MANE Select: NM_203447
dbSNP: rs372858877
Type: single nucleotide variant
Location: chr9:372194 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.17
Residue 673: 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

Also linked: hyper-IgE recurrent infection syndrome 3, autosomal recessive

For Combined immunodeficiency due to DOCK8 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

DOCK8 p.Ile673Leu Uncertain significance ★ ⚠ same residue
DOCK8 p.Ile673Met Uncertain significance ★ ⚠ same residue
DOCK8 p.Ile673Val 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

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-ile673phe (accessed [today's date]).

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