Is CYBA p.Arg56fs (c.166dup) pathogenic?

CYBA p.Arg56fs (c.166dup) is classified Pathogenic in CYBA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-20). Very rare (popmax 0.00119%, nfe); Associated with chronic granulomatous disease.

What condition is associated with CYBA p.Arg56fs (c.166dup)?

CYBA p.Arg56fs (c.166dup) is associated with chronic granulomatous disease, granulomatous disease, chronic, autosomal recessive, cytochrome b-negative (ClinVar).

How common is CYBA p.Arg56fs (c.166dup) in the general population?

CYBA p.Arg56fs (c.166dup) is very rare (popmax 0.00119%, nfe) (gnomAD).

How is Chronic granulomatous disease inherited?

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

CYBA p.Arg56fs

c.166dup · rs1352931329 · VCV1072119

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Conditions

chronic granulomatous disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.5	GERP 1.4, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% European (non-Finnish) · 14/1,179,722 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00096% 14/1,458,854 alleles · very rare

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: CYBA
Protein: p.Arg56fs
Coding: c.166dup
MANE Select: NM_000101
dbSNP: rs1352931329
Type: Duplication
Location: chr16:88647137 (GRCh38)
Gene constraint: LOEUF 1.726 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.28 · 7 PDB

Full CYBA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

chronic granulomatous disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: granulomatous disease, chronic, autosomal recessive, cytochrome b-negative

For Chronic granulomatous disease (Orphanet):

Inheritance: Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

CYBA p.Arg56Gly Uncertain significance ★★ ⚠ same residue
CYBA p.Arg56Gln Uncertain significance ★ ⚠ same residue
CYBA p.Arg56Leu Uncertain significance ★ ⚠ same residue
CYBA p.Arg56Trp Uncertain significance ★ ⚠ same residue
CYBA p.Arg56= Likely benign ★ same residue
CYBA p.Pro157fs Pathogenic/Likely pathogenic ★★ same condition
CYBA c.204-9_204-3dup Likely benign ★★ same condition
CYBA p.Ala106fs 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/cyba-p-arg56fs (accessed [today's date]).

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