Is CYBB p.Arg226Ter (c.676C>T) pathogenic?

CYBB p.Arg226Ter (c.676C>T) is classified Pathogenic in CYBB (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-10-31). Very rare (popmax 0.00176%, afr); Associated with CYBB-related disorders.

What condition is associated with CYBB p.Arg226Ter (c.676C>T)?

CYBB p.Arg226Ter (c.676C>T) is associated with CYBB-related disorders, granulomatous disease, chronic, X-linked, chronic granulomatous disease (ClinVar).

How common is CYBB p.Arg226Ter (c.676C>T) in the general population?

CYBB p.Arg226Ter (c.676C>T) is very rare (popmax 0.00176%, afr) (gnomAD).

CYBB p.Arg226Ter

c.676C>T · rs137854592 · VCV10929

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00176%, afr)

Conditions

CYBB-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 7 of 13
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.83	GERP 1.3, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00176% African / African-American · 1/56,935 alleles

Overall 0.000895% 1/111,757 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.Arg226Ter
Coding: c.676C>T
MANE Select: NM_000397
dbSNP: rs137854592
Type: single nucleotide variant
Location: chrX:37798956 (GRCh38)
Structure: AlphaFold pLDDT 90.29 · 6 PDB
Residue 226: the ferric oxidoreductase domain; a binding site

Full CYBB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CYBB-related disorders

Also linked: granulomatous disease, chronic, X-linked chronic granulomatous disease

Similar variants

CYBB p.Arg226Gln Uncertain significance ★ ⚠ same residue
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

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-arg226ter (accessed [today's date]).

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