# NM_000397.4(CYBB):c.772C>G (p.Pro258Ala)

https://sugi.bio/variant/cybb-p-pro258ala

## Summary

**CYBB p.Pro258Ala (c.772C>G)** is classified **Uncertain significance** in CYBB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-20). AlphaMissense: likely benign (0.2414); Very rare (popmax 0.000112%, nfe); Associated with granulomatous disease, chronic, X-linked.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1384465552 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.000112%, nfe)

## For patients & families {#patients}

This is a change in the CYBB gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Pro258Ala |
| Coding change (HGVS c.) | c.772C>G |
| MANE Select transcript | [NM_000397](https://www.ncbi.nlm.nih.gov/nuccore/NM_000397) |
| dbSNP | [rs1384465552](https://www.ncbi.nlm.nih.gov/snp/rs1384465552/) |
| Variant type | single nucleotide variant |
| Location | chrX:37799052-37799052 (GRCh38) |
| ClinVar | [VCV1505442](https://www.ncbi.nlm.nih.gov/clinvar/variation/1505442/) |

**All HGVS expressions:** `LRG_53:g.24032C>G`, `LRG_53t1:c.772C>G`, `NC_000023.10:g.37658305C>G`, `NC_000023.11:g.37799052C>G`, `NG_009065.1:g.24032C>G`, `NM_000397.4:c.772C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.2414)
- REVEL 0.487 (indeterminate)
- SaProt LLR -8.998 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 1.864, GERP 0.429, phastCons 0.617 — weakly conserved position
- CADD: **PHRED 10.21**. 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 1.17** across the covering region of the MANE Select transcript (37,796,078–37,801,327), spanning 5,249 bp. Chi-square p 0.15. 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 (gnomAD v4.1): grpmax **0.000112%** (nfe) · 1/892,323 in the highest group · 1/111,543 alleles overall — very rare (popmax 0.000112%, nfe).

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

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.Pro258Ala 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-04-20.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-20 |

## Associated conditions {#conditions}

[granulomatous disease, chronic, X-linked](https://sugi.bio/atlas/disease/granulomatous-disease-chronic-x-linked/), [X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency](https://sugi.bio/atlas/disease/x-linked-mendelian-susceptibility-to-mycobacterial-diseases-due-to-cybb-deficiency/).

**Reported phenotype names (ClinVar):** Granulomatous disease, chronic, X-linked, X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency, CYTOCHROME b-NEGATIVE GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, SOMATIC MOSAIC, IMMUNODEFICIENCY 34, IMMUNODEFICIENCY 34, MYCOBACTERIOSIS, 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 1505442). 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.*