# NM_000397.4(CYBB):c.698C>T (p.Ala233Val)

https://sugi.bio/variant/cybb-p-ala233val

## Summary

**CYBB p.Ala233Val (c.698C>T)** is classified **Conflicting classifications of pathogenicity** in CYBB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-09-08). AlphaMissense: likely benign (0.0985); Very rare (popmax 0.000224%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs782174347 · 3 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.000224%, nfe)

## For patients & families {#patients}

This is a change in the CYBB gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to Inborn genetic diseases.

*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.*

**Support & next steps:** [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.Ala233Val |
| Coding change (HGVS c.) | c.698C>T |
| MANE Select transcript | [NM_000397](https://www.ncbi.nlm.nih.gov/nuccore/NM_000397) |
| dbSNP | [rs782174347](https://www.ncbi.nlm.nih.gov/snp/rs782174347/) |
| Variant type | single nucleotide variant |
| Location | chrX:37798978-37798978 (GRCh38) |
| ClinVar | [VCV1017273](https://www.ncbi.nlm.nih.gov/clinvar/variation/1017273/) |

**All HGVS expressions:** `LRG_53:g.23958C>T`, `NC_000023.10:g.37658231C>T`, `NC_000023.11:g.37798978C>T`, `NG_009065.1:g.23958C>T`, `NM_000397.3:c.698C>T`, `NM_000397.4:c.698C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0985)
- REVEL 0.262 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.631 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -3.03, GERP -2.62 — fast-evolving / accelerated position
- CADD: **PHRED 0.003**. 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 deltas (raw): acceptor loss **0.21**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.21**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.000224%** (nfe) · FAF95 3.7e-05% · FAF99 1.4e-05% · 2/892,879 in the highest group · 2/1,206,584 alleles overall — very rare (popmax 0.000224%, 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 **233** 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.Ala233Val 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-09-08.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely benign).

**Submission history:** 3 submissions (2021–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2021-04-21 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-09-08 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [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):** Inborn genetic diseases, Granulomatous disease, chronic, X-linked, Chronic granulomatous disease, CYTOCHROME b-NEGATIVE GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, SOMATIC MOSAIC.

## Similar variants {#similar}

Related CYBB variant pages (same residue, condition, or type): [CYBB p.Ala233Thr](/variant/cybb-p-ala233thr), [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), [CYBB c.483+3A>T](/variant/cybb-c-483-plus-3a-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 1017273). 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.*