# NM_000101.4(CYBA):c.134C>T (p.Ala45Val)

https://sugi.bio/variant/cyba-p-ala45val

## Summary

**CYBA p.Ala45Val (c.134C>T)** is classified **Uncertain significance** in CYBA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-22). AlphaMissense: ambiguous (0.3838); Very rare (popmax 0.00667%, amr); Associated with granulomatous disease, chronic, autosomal recessive, cytochrome b-negative.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs776963412 · 3 submitters · 2 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.00667%, amr)

## For patients & families {#patients}

This is a change in the CYBA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to granulomatous disease, chronic, autosomal recessive, cytochrome b-negative.

*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) |
| Diagnostic panels | CYBA is a diagnostic-grade gene on 4 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/0015175/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CYBA](https://sugi.bio/atlas/gene/CYBA/) |
| Protein change (HGVS p.) | p.Ala45Val |
| Coding change (HGVS c.) | c.134C>T |
| MANE Select transcript | [NM_000101](https://www.ncbi.nlm.nih.gov/nuccore/NM_000101) |
| dbSNP | [rs776963412](https://www.ncbi.nlm.nih.gov/snp/rs776963412/) |
| Variant type | single nucleotide variant |
| Location | chr16:88647170-88647170 (GRCh38) |
| ClinVar | [VCV968606](https://www.ncbi.nlm.nih.gov/clinvar/variation/968606/) |

**All HGVS expressions:** `LRG_52:g.8880C>T`, `NC_000016.10:g.88647170G>A`, `NC_000016.9:g.88713578G>A`, `NG_007291.1:g.8880C>T`, `NM_000101.2:c.134C>T`, `NM_000101.4:c.134C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.3838) — no call either way
- REVEL 0.639 (indeterminate)
- SaProt LLR -7.728 (tolerated)
- Conservation: phyloP 11.485, GERP 1.38, phastCons 1 — highly conserved
- CADD: **PHRED 25.9**. 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 1.20** across the covering region of the MANE Select transcript (88,643,356–88,651,013), spanning 7,657 bp. Chi-square p 0.00077. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.33 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 **0.00667%** (amr) · FAF95 0.00226% · FAF99 0.00156% · 4/59,990 in the highest group · 39/1,611,890 alleles overall — very rare (popmax 0.00667%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00667% | 14,997 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,821 |
| European (non-Finnish) | 0.00254% | 39,328 |
| South Asian | 0.0022% | 45,524 |

*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}

**CYBA** population constraint: LOEUF 1.726, pLI 2.5895e-10, missense-Z -2.4309. *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 **45** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 77.28, 40% of residues very-high.

**7 experimental structure(s)** (PDB): [1WLP](https://www.rcsb.org/structure/1WLP), [7U8G](https://www.rcsb.org/structure/7U8G), [7YXW](https://www.rcsb.org/structure/7YXW), [8GZ3](https://www.rcsb.org/structure/8GZ3), [8KEI](https://www.rcsb.org/structure/8KEI), [8WEJ](https://www.rcsb.org/structure/8WEJ) — incl. mutant structure 7YXW.

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

*Describes the biological roles of CYBA (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:** CYBA's established molecular role includes electron transfer activity. In Reactome, CYBA is annotated in disease pathway(s) including **WNT5:FZD7-mediated leishmania damping**.

**Disease mechanism (Reactome):** CYBA loss or alteration is curated in [WNT5:FZD7-mediated leishmania damping](https://reactome.org/content/detail/R-HSA-9673324).

### Pathways affected {#pathways}

CYBA participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [WNT5:FZD7-mediated leishmania damping](https://reactome.org/content/detail/R-HSA-9673324) | curated |
| [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:** electron transfer activity, SH3 domain binding, protein heterodimerization activity.

**Biological process:** superoxide metabolic process, inflammatory response, cytochrome complex assembly, positive regulation of interleukin-6 production, positive regulation of tumor necrosis factor production, positive regulation of toll-like receptor 2 signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-22.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2020–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-23 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-03-04 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-22 |

## Associated conditions {#conditions}

[granulomatous disease, chronic, autosomal recessive, cytochrome b-negative](https://sugi.bio/atlas/disease/granulomatous-disease-chronic-autosomal-recessive-cytochrome-b-negative/), [chronic granulomatous disease](https://sugi.bio/atlas/disease/chronic-granulomatous-disease/).

**Reported phenotype names (ClinVar):** Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative, Chronic granulomatous disease, Inborn genetic diseases, CGD DUE TO DEFICIENCY OF THE ALPHA SUBUNIT OF CYTOCHROME b, CGD, AUTOSOMAL RECESSIVE CYTOCHROME b-NEGATIVE, CYBA DEFICIENCY, GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, 4, Chronic granulomatous disease, autosomal, due to deficiency of CYBA.

## Similar variants {#similar}

Related CYBA variant pages (same residue, condition, or type): [CYBA p.Ala45=](/variant/cyba-p-ala45), [CYBA c.128+2T>C](/variant/cyba-c-128-plus-2t-c), [CYBA c.204-2A>G](/variant/cyba-c-204-minus-2a-g), [CYBA c.287+1G>T](/variant/cyba-c-287-plus-1g-t), [CYBA c.287+2T>C](/variant/cyba-c-287-plus-2t-c), [CYBA c.288-1G>T](/variant/cyba-c-288-minus-1g-t), [CYBA c.369+1G>A](/variant/cyba-c-369-plus-1g-a), [CYBA c.58+2T>C](/variant/cyba-c-58-plus-2t-c).

### 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 968606). 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.*