Is CYBB p.Trp516Arg (c.1546T>A) pathogenic?

CYBB p.Trp516Arg (c.1546T>A) is classified Pathogenic in CYBB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-28). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1; Associated with granulomatous disease, chronic, X-linked.

What condition is associated with CYBB p.Trp516Arg (c.1546T>A)?

CYBB p.Trp516Arg (c.1546T>A) is associated with granulomatous disease, chronic, X-linked (ClinVar).

How common is CYBB p.Trp516Arg (c.1546T>A) in the general population?

CYBB p.Trp516Arg (c.1546T>A) is absent from gnomAD v4.1 (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.Trp516Arg (c.1546T>A)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

CYBB p.Trp516Arg

c.1546T>A · rs151344487 · VCV2138525

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

granulomatous disease, chronic, X-linked

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic ✓ concordant with ClinVar · top 1% in CYBB
REVEL	0.877	moderately pathogenic-leaning
SaProt	LLR -13.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 0.66, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 9,586 bp · p 2.3e-09 · regional, not allelic
Overall
CADD	26.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CYBB
Protein: p.Trp516Arg
Coding: c.1546T>A
MANE Select: NM_000397
dbSNP: rs151344487
Type: single nucleotide variant
Location: chrX:37809651 (GRCh38)
Structure: AlphaFold pLDDT 90.29 · 6 PDB
Residue 516: a UniProt-annotated variant site (in cgdx); 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 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
CYBB p.Ala156Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
CYBB p.Ala57Glu 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-trp516arg (accessed [today's date]).

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