Is CYBB p.Arg559Gln (c.1676G>A) pathogenic?

CYBB p.Arg559Gln (c.1676G>A) is classified Likely benign in CYBB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-18). AlphaMissense: likely benign (0.0839); Very rare (popmax 0.00291%, nfe); Associated with granulomatous disease, chronic, X-linked.

What condition is associated with CYBB p.Arg559Gln (c.1676G>A)?

CYBB p.Arg559Gln (c.1676G>A) is associated with granulomatous disease, chronic, X-linked (ClinVar).

How common is CYBB p.Arg559Gln (c.1676G>A) in the general population?

CYBB p.Arg559Gln (c.1676G>A) is very rare (popmax 0.00291%, 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.

What do computational predictors say about CYBB p.Arg559Gln (c.1676G>A)?

AlphaMissense predicts likely benign (score 0.0839) — an in-silico prediction, not a clinical call.

CYBB p.Arg559Gln

c.1676G>A · rs763640811 · VCV1142807

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0839 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00291%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

granulomatous disease, chronic, X-linked

Computational evidence

Protein change
AlphaMissense	0.0839	likely benign
REVEL	0.612	indeterminate
SaProt	LLR -4.89	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 9,586 bp · p 2.3e-09 · regional, not allelic
Overall
CADD	26.4	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 0.00291% European (non-Finnish) · 26/892,148 alleles

Filtering AF 0.00203% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00172%

Overall 0.00329% 36/1,094,238 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0189%	5,279
European (non-Finnish)grpmax	0.00291%	34,313
Finnishnot grpmax-eligible	0.00214%	46,701

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg559Gln
Coding: c.1676G>A
MANE Select: NM_000397
dbSNP: rs763640811
Type: single nucleotide variant
Location: chrX:37810880 (GRCh38)
Structure: AlphaFold pLDDT 90.29 · 6 PDB
Residue 559: a β-strand

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.Arg559Trp Uncertain significance ★ ⚠ same residue
CYBB p.Arg559= Likely benign ★ 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-arg559gln (accessed [today's date]).

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