Is DOCK8 p.Leu794Pro (c.2381T>C) pathogenic?

DOCK8 p.Leu794Pro (c.2381T>C) is classified Uncertain significance in DOCK8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-18). AlphaMissense: likely pathogenic (0.5646); Ultra-rare (popmax 0.0176%, mid); Associated with hyper-IgE recurrent infection syndrome 3, autosomal recessive.

What condition is associated with DOCK8 p.Leu794Pro (c.2381T>C)?

DOCK8 p.Leu794Pro (c.2381T>C) is associated with hyper-IgE recurrent infection syndrome 3, autosomal recessive (ClinVar).

How common is DOCK8 p.Leu794Pro (c.2381T>C) in the general population?

DOCK8 p.Leu794Pro (c.2381T>C) is ultra-rare (popmax 0.0176%, mid) (gnomAD).

What do computational predictors say about DOCK8 p.Leu794Pro (c.2381T>C)?

AlphaMissense predicts likely pathogenic (score 0.5646) — an in-silico prediction, not a clinical call.

DOCK8 p.Leu794Pro

Q: How is Autosomal recessive hyper-IgE syndrome due to ZNF341 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.2381T>C · rs769117348 · VCV1677151

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5646 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyper-IgE recurrent infection syndrome 3, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.5646	likely pathogenic
REVEL	0.224	benign-leaning
SaProt	LLR -9.34	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.4, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	24.0	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 0.0176% Middle Eastern · 1/5,694 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000275% 4/1,454,234 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0176%	5,694
Admixed American	0.005%	19,995

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.Leu794Pro
Coding: c.2381T>C
MANE Select: NM_203447
dbSNP: rs769117348
Type: single nucleotide variant
Location: chr9:377152 (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

hyper-IgE recurrent infection syndrome 3, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive hyper-IgE syndrome due to ZNF341 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

DOCK8 p.Leu794= Likely benign ★ same residue
DOCK8 p.Ala13Pro Uncertain significance ★★ ⚠ same condition
DOCK8 p.Ala1761Val Uncertain significance ★★ ⚠ same condition
DOCK8 p.Ala229Asp Uncertain significance ★★ ⚠ same condition
DOCK8 p.Arg1015Cys Uncertain significance ★★ ⚠ same condition
DOCK8 p.Arg1238Cys Uncertain significance ★★ ⚠ same condition
DOCK8 p.Arg1294Cys Uncertain significance ★★ ⚠ same condition
DOCK8 p.Arg1904Gln Uncertain significance ★★ ⚠ 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-leu794pro (accessed [today's date]).

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