Is CYBB p.Pro539= (c.1617T>C) pathogenic?

CYBB p.Pro539= (c.1617T>C) is classified Benign in CYBB (ClinVar, Single submitter, 2 submitters; last evaluated 2025-05-11). Ultra-rare (popmax 0.0547%, amr); Associated with granulomatous disease, chronic, X-linked.

What condition is associated with CYBB p.Pro539= (c.1617T>C)?

CYBB p.Pro539= (c.1617T>C) is associated with granulomatous disease, chronic, X-linked, chronic granulomatous disease (ClinVar).

How common is CYBB p.Pro539= (c.1617T>C) in the general population?

CYBB p.Pro539= (c.1617T>C) is ultra-rare (popmax 0.0547%, 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.

CYBB p.Pro539=

c.1617T>C · rs187038548 · VCV991715

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0547%, amr)

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 -3.6	GERP 0.47
Overall
CADD	5.778	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0547% Admixed American · 25/45,722 alleles

Filtering AF 0.038% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0324%

Overall 0.00207% 25/1,206,474 alleles · ultra-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.Pro539=
Coding: c.1617T>C
MANE Select: NM_000397
dbSNP: rs187038548
Type: single nucleotide variant
Location: chrX:37810821 (GRCh38)
Structure: AlphaFold pLDDT 90.29 · 6 PDB

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

Also linked: chronic granulomatous disease

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.1151+2T>C Pathogenic ★★ same condition
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

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-pro539 (accessed [today's date]).

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