Is DOCK8 p.Leu50Phe (c.148C>T) pathogenic?

DOCK8 p.Leu50Phe (c.148C>T) is classified Uncertain significance in DOCK8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-13). AlphaMissense: likely benign (0.0712); Ultra-rare (popmax 0.0166%, mid); Associated with hyper-IgE recurrent infection syndrome 3, autosomal recessive.

What condition is associated with DOCK8 p.Leu50Phe (c.148C>T)?

DOCK8 p.Leu50Phe (c.148C>T) is associated with hyper-IgE recurrent infection syndrome 3, autosomal recessive (ClinVar).

How common is DOCK8 p.Leu50Phe (c.148C>T) in the general population?

DOCK8 p.Leu50Phe (c.148C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about DOCK8 p.Leu50Phe (c.148C>T)?

AlphaMissense predicts likely benign (score 0.0712) — an in-silico prediction, not a clinical call.

DOCK8 p.Leu50Phe

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.148C>T · rs1045835531 · VCV858726

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0712 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyper-IgE recurrent infection syndrome 3, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.0712	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -7.18	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 4.1	GERP 1.7, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 235 kb · p 6.4e-14 · regional, not allelic
Overall
CADD	19.46	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,016 alleles

Filtering AF 0.00344% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00311%

Overall 0.00348% 54/1,550,504 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,016
European (non-Finnish)	0.00445%	22,466
Admixed American	0.00196%	50,922
Remaining individualsnot grpmax-eligible	0.00166%	60,194

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.Leu50Phe
Coding: c.148C>T
MANE Select: NM_203447
dbSNP: rs1045835531
Type: single nucleotide variant
Location: chr9:271721 (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.Leu50= 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-leu50phe (accessed [today's date]).

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