Is CYBB p.Gln526His (c.1578A>C) pathogenic?

CYBB p.Gln526His (c.1578A>C) is classified Uncertain significance in CYBB (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-02-04). AlphaMissense: likely benign (0.117); Very rare (popmax 0.00177%, sas); Associated with chronic granulomatous disease.

What condition is associated with CYBB p.Gln526His (c.1578A>C)?

CYBB p.Gln526His (c.1578A>C) is associated with chronic granulomatous disease (ClinVar).

How common is CYBB p.Gln526His (c.1578A>C) in the general population?

CYBB p.Gln526His (c.1578A>C) is very rare (popmax 0.00177%, sas) (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.Gln526His (c.1578A>C)?

AlphaMissense predicts likely benign (score 0.117) — an in-silico prediction, not a clinical call.

CYBB p.Gln526His

c.1578A>C · VCV4065621

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.117 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00177%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

chronic granulomatous disease

Computational evidence

Protein change
AlphaMissense	0.117	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -7.75	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 2.7	GERP -0.74, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 9,586 bp · p 2.3e-09 · regional, not allelic
Overall
CADD	15.63	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 0.00177% South Asian · 1/56,586 alleles

Overall 9.12e-05% 1/1,096,117 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: CYBB
Protein: p.Gln526His
Coding: c.1578A>C
MANE Select: NM_000397
Type: single nucleotide variant
Location: chrX:37809683 (GRCh38)
Structure: AlphaFold pLDDT 90.29 · 6 PDB
Residue 526: an α-helix

Full CYBB 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

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.Gln526= Likely benign ★ same residue
CYBB c.1151+2T>C Pathogenic ★★ same condition
CYBB c.483+1G>T Pathogenic ★★ same condition
CYBB c.483+3A>T Likely pathogenic ★★ same condition
CYBB p.Arg226Ter Pathogenic ★★ same condition
CYBB p.Glu203Ter Pathogenic/Likely pathogenic ★★ same condition
CYBB p.Ala417Thr Uncertain significance ★★ ⚠ same condition
CYBB p.Ala431Thr 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/cybb-p-gln526his (accessed [today's date]).

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