Is CYBB p.Gln459= (c.1377A>G) pathogenic?

CYBB p.Gln459= (c.1377A>G) is classified Benign in CYBB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-28). Ultra-rare (popmax 0.0474%, eas); Associated with granulomatous disease, chronic, X-linked.

What condition is associated with CYBB p.Gln459= (c.1377A>G)?

CYBB p.Gln459= (c.1377A>G) is associated with granulomatous disease, chronic, X-linked (ClinVar).

How common is CYBB p.Gln459= (c.1377A>G) in the general population?

CYBB p.Gln459= (c.1377A>G) is ultra-rare (popmax 0.0474%, eas) (gnomAD).

How is Chronic granulomatous disease inherited?

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

CYBB p.Gln459=

c.1377A>G · rs782413959 · VCV1169680

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0474%, eas)

Conditions

granulomatous disease, chronic, X-linked

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP -3.8, phastCons 1
Overall
CADD	7.245	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0474% East Asian · 16/33,735 alleles

Filtering AF 0.0297% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0242%

Overall 0.00141% 17/1,207,126 alleles · ultra-rare exomes 13/1,095,618 · genomes 4/111,508 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0474%	2,108
Remaining individualsnot grpmax-eligible	0.0021%	47,519

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: CYBB
Protein: p.Gln459=
Coding: c.1377A>G
MANE Select: NM_000397
dbSNP: rs782413959
Type: single nucleotide variant
Location: chrX:37806449 (GRCh38)
Structure: AlphaFold pLDDT 90.29 · 6 PDB
Residue 459: an α-helix

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

Disease context

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

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

CYBB p.Gln459Arg Uncertain significance ★ ⚠ same residue
CYBB p.Gln459Ter Pathogenic ★ same residue
CYBB c.1315-2A>G Pathogenic/Likely pathogenic ★★ same condition
CYBB c.141+1G>T Pathogenic ★★ same condition
CYBB c.252+5G>A Pathogenic ★★ same condition
CYBB c.483+1G>A Pathogenic ★★ same condition
CYBB c.483+1G>T Pathogenic ★★ same condition
CYBB c.483+3A>T 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/cybb-p-gln459 (accessed [today's date]).

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