# NM_000397.4(CYBB):c.388C>A (p.Arg130=)

https://sugi.bio/variant/cybb-p-arg130

## Summary

**CYBB p.Arg130= (c.388C>A)** is classified **Likely benign** in CYBB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-13). Ultra-rare (popmax 0.0923%, mid); Associated with granulomatous disease, chronic, X-linked.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs180899069 · 4 submitters · 2 linked conditions · ultra-rare (popmax 0.0923%, mid)

## For patients & families {#patients}

This is a change in the CYBB gene that is classified as likely benign — not considered disease-causing, submitted by 4 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.Arg130= |
| Coding change (HGVS c.) | c.388C>A |
| MANE Select transcript | [NM_000397](https://www.ncbi.nlm.nih.gov/nuccore/NM_000397) |
| dbSNP | [rs180899069](https://www.ncbi.nlm.nih.gov/snp/rs180899069/) |
| Variant type | single nucleotide variant |
| Location | chrX:37793715-37793715 (GRCh38) |
| ClinVar | [VCV1156899](https://www.ncbi.nlm.nih.gov/clinvar/variation/1156899/) |

**All HGVS expressions:** `LRG_53:g.18695C>A`, `NC_000023.10:g.37652968C>A`, `NC_000023.11:g.37793715C>A`, `NG_009065.1:g.18695C>A`, `NM_000397.3:c.388C>A`, `NM_000397.4:c.388C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 2.627, GERP 0.763, phastCons 0.996 — highly conserved position (PP3-type support)
- CADD: **PHRED 7.174**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.20 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0923%** (mid) · FAF95 0.0315% · FAF99 0.019% · 4/4,335 in the highest group · 33/1,204,609 alleles overall — ultra-rare (popmax 0.0923%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0923% | 1,084 |
| African / African-American | 0.0335% | 2,988 |
| Remaining individuals (not grpmax-eligible) | 0.0148% | 6,774 |
| South Asian | 0.00353% | 28,342 |
| European (non-Finnish) | 0.000112% | 891,417 |

*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 **130** lies in an α-helix; the ferric oxidoreductase domain.

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.Arg130= falls in the ferric oxidoreductase 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-13.

**Submitter consensus:** unanimous (4/4 Likely benign).

**Submission history:** 4 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2021-08-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-13 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-03-12 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Granulomatous disease, chronic, X-linked, Chronic granulomatous disease, CYBB-related disorder, not specified, CYBB-related condition, AllHighlyPenetrant, GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, SOMATIC MOSAIC, CYTOCHROME b-NEGATIVE GRANULOMATOUS DISEASE, CHRONIC, X-LINKED.

## Same-residue context {#hotspot}

Residue **130** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [CYBB p.Arg130fs](/variant/cybb-p-arg130fs), [CYBB p.Arg130Pro](/variant/cybb-p-arg130pro), [CYBB p.Arg130Ter](/variant/cybb-p-arg130ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CYBB variant pages (same residue, condition, or type): [CYBB p.Arg130Pro](/variant/cybb-p-arg130pro), [CYBB p.Arg130Ter](/variant/cybb-p-arg130ter), [CYBB c.1151+2T>C](/variant/cybb-c-1151-plus-2t-c), [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).

### 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 1156899). 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.*