Is CYBB p.Arg513Trp (c.1537C>T) pathogenic?

CYBB p.Arg513Trp (c.1537C>T) is classified Uncertain significance in CYBB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-24). AlphaMissense: likely pathogenic (0.9611); Very rare (popmax 0.00221%, amr); Associated with granulomatous disease, chronic, X-linked.

What condition is associated with CYBB p.Arg513Trp (c.1537C>T)?

CYBB p.Arg513Trp (c.1537C>T) is associated with granulomatous disease, chronic, X-linked (ClinVar).

How common is CYBB p.Arg513Trp (c.1537C>T) in the general population?

CYBB p.Arg513Trp (c.1537C>T) is very rare (popmax 0.00221%, amr) (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.Arg513Trp (c.1537C>T)?

AlphaMissense predicts likely pathogenic (score 0.9611) — an in-silico prediction, not a clinical call.

CYBB p.Arg513Trp

c.1537C>T · rs1804084723 · VCV3019925

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9611 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

granulomatous disease, chronic, X-linked

Computational evidence

Protein change
AlphaMissense	0.9611	likely pathogenic
REVEL	0.874	moderately pathogenic-leaning
SaProt	LLR -13.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.8	GERP -0.087, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 9,586 bp · p 2.3e-09 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00221% Admixed American · 1/45,347 alleles

Overall 0.000897% 1/111,469 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.Arg513Trp
Coding: c.1537C>T
MANE Select: NM_000397
dbSNP: rs1804084723
Type: single nucleotide variant
Location: chrX:37809642 (GRCh38)
Structure: AlphaFold pLDDT 90.29 · 6 PDB
Residue 513: a binding site

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.Arg513Gln Uncertain significance ★ ⚠ same residue
CYBB p.Arg513= 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-arg513trp (accessed [today's date]).

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