# NM_000397.4(CYBB):c.911C>G (p.Pro304Arg)

https://sugi.bio/variant/cybb-p-pro304arg

## Summary

**CYBB p.Pro304Arg (c.911C>G)** is classified **Pathogenic** in CYBB (ClinVar, No assertion criteria, 2 submitters; last evaluated 2004-10-01). AlphaMissense: likely pathogenic (0.7913); Absent from gnomAD v4.1; Associated with granulomatous disease, chronic, X-linked.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs137854596 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CYBB gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to granulomatous disease, chronic, X-linked.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CYBB is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Chronic granulomatous disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Sinusitis — Very frequent (99-80%)
- Otitis media — Very frequent (99-80%)
- Cutaneous photosensitivity — Very frequent (99-80%)
- Hypermelanotic macule — Very frequent (99-80%)
- Abnormality of neutrophils — Very frequent (99-80%)
- Fever — Very frequent (99-80%)
- Pyloric stenosis — Very frequent (99-80%)
- Malabsorption — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015294/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CYBB](https://sugi.bio/atlas/gene/CYBB/) |
| Protein change (HGVS p.) | p.Pro304Arg |
| Coding change (HGVS c.) | c.911C>G |
| MANE Select transcript | [NM_000397](https://www.ncbi.nlm.nih.gov/nuccore/NM_000397) |
| dbSNP | [rs137854596](https://www.ncbi.nlm.nih.gov/snp/rs137854596/) |
| Variant type | single nucleotide variant |
| Location | chrX:37803890-37803890 (GRCh38) |
| ClinVar | [VCV10927](https://www.ncbi.nlm.nih.gov/clinvar/variation/10927/) |

**All HGVS expressions:** `LRG_53:g.28874C>G`, `LRG_53t1:c.911C>G`, `NC_000023.10:g.37663143C>G`, `NC_000023.11:g.37803890C>G`, `NG_009065.1:g.28874C>G`, `NM_000397.4:c.911C>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.7913) — concordant with the pathogenic call
- REVEL 0.951 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -8.825 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 7.65, GERP 1.88, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.9**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.59** across the covering region of the MANE Select transcript (37,801,328–37,810,914), spanning 9,586 bp. Chi-square p 2.3e-09. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CYBB** population constraint: ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **304** lies in a turn; the fad-binding fr-type domain; a UniProt-annotated variant site (in cgdx; reduces nadph oxidase activity to 4% of wild-type; translocation to the membrane of the phagosome is only attenuated).

AlphaFold model confidence (whole protein): pLDDT 90.29, 70% of residues very-high.

**6 experimental structure(s)** (PDB): [3A1F](https://www.rcsb.org/structure/3A1F), [7U8G](https://www.rcsb.org/structure/7U8G), [8GZ3](https://www.rcsb.org/structure/8GZ3), [8KEI](https://www.rcsb.org/structure/8KEI), [8WEJ](https://www.rcsb.org/structure/8WEJ), [8X2L](https://www.rcsb.org/structure/8X2L).

## What this gene does {#gene-function}

*Describes the biological roles of CYBB (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CYBB's established molecular role includes heme binding. p.Pro304Arg falls in the fad-binding fr-type domain.


### Pathways affected {#pathways}

CYBB participates in **9 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cross-presentation of particulate exogenous antigens (phagosomes)](https://reactome.org/content/detail/R-HSA-1236973) | curated |
| [Detoxification of Reactive Oxygen Species](https://reactome.org/content/detail/R-HSA-3299685) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |
| [RHO GTPases Activate NADPH Oxidases](https://reactome.org/content/detail/R-HSA-5668599) | curated |
| [ROS and RNS production in phagocytes](https://reactome.org/content/detail/R-HSA-1222556) | curated |
| [VEGFA-VEGFR2 Pathway](https://reactome.org/content/detail/R-HSA-4420097) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** heme binding, protein heterodimerization activity, flavin adenine dinucleotide binding, NADPH binding, FAD binding, superoxide-generating NADPH oxidase activity.

**Biological process:** superoxide metabolic process, superoxide anion generation, innate immune response, respiratory burst.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2004-10-01.

**Submitter consensus:** conflicting (1 not provided, 1 Pathogenic).

**Submission history:** 2 submissions (2004); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| UniProtKB/Swiss-Prot | not provided | no classification provided | not provided |  |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2004-10-01 |

## Associated conditions {#conditions}

[granulomatous disease, chronic, X-linked](https://sugi.bio/atlas/disease/granulomatous-disease-chronic-x-linked/).

**Reported phenotype names (ClinVar):** Granulomatous disease, chronic, X-linked, not provided, none provided, GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, SOMATIC MOSAIC, CYTOCHROME b-NEGATIVE GRANULOMATOUS DISEASE, CHRONIC, X-LINKED.

## Similar variants {#similar}

Related CYBB variant pages (same residue, condition, or type): [CYBB c.1315-2A>G](/variant/cybb-c-1315-minus-2a-g), [CYBB c.141+1G>T](/variant/cybb-c-141-plus-1g-t), [CYBB c.252+5G>A](/variant/cybb-c-252-plus-5g-a), [CYBB c.483+1G>A](/variant/cybb-c-483-plus-1g-a), [CYBB c.483+1G>T](/variant/cybb-c-483-plus-1g-t), [CYBB c.483+3A>T](/variant/cybb-c-483-plus-3a-t), [CYBB p.Ala156Thr](/variant/cybb-p-ala156thr), [CYBB p.Ala57Glu](/variant/cybb-p-ala57glu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 10927). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*