Is CYBB p.Arg229His (c.686G>A) pathogenic?

CYBB p.Arg229His (c.686G>A) is classified Benign/Likely benign in CYBB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-19). AlphaMissense: likely pathogenic (0.764); Rare (popmax 0.38%, afr); Associated with granulomatous disease, chronic, X-linked.

What condition is associated with CYBB p.Arg229His (c.686G>A)?

CYBB p.Arg229His (c.686G>A) is associated with granulomatous disease, chronic, X-linked, chronic granulomatous disease (ClinVar).

How common is CYBB p.Arg229His (c.686G>A) in the general population?

CYBB p.Arg229His (c.686G>A) is rare (popmax 0.38%, afr) (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.Arg229His (c.686G>A)?

AlphaMissense predicts likely pathogenic (score 0.764) — an in-silico prediction, not a clinical call.

CYBB p.Arg229His

c.686G>A · rs139670417 · VCV533561

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.764 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.38%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

granulomatous disease, chronic, X-linked

Computational evidence

Protein change
AlphaMissense	0.764	likely pathogenic
REVEL	0.911	moderately pathogenic-leaning
SaProt	LLR -10.07	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 10	GERP 1.3, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 5,249 bp · p 0.15 · regional, not allelic
Overall
CADD	27.0	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

Grpmax group 0.38% African / African-American · 217/57,091 alleles

Filtering AF 0.339% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.323%

Overall 0.0246% 297/1,205,587 alleles · rare exomes 182/1,093,735 · genomes 115/111,852 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.38%	263
Ashkenazi Jewishnot grpmax-eligible	0.105%	953
Admixed American	0.0373%	2,677
Remaining individualsnot grpmax-eligible	0.0211%	4,739
East Asian	0.00596%	16,776
European (non-Finnish)	0.00314%	31,863

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.Arg229His
Coding: c.686G>A
MANE Select: NM_000397
dbSNP: rs139670417
Type: single nucleotide variant
Location: chrX:37798966 (GRCh38)
Structure: AlphaFold pLDDT 90.29 · 6 PDB
Residue 229: a β-strand; the ferric oxidoreductase domain

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-arg229his (accessed [today's date]).

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