# NM_031938.7(BCO2):c.1459C>T (p.Arg487Trp)

https://sugi.bio/variant/bco2-p-arg487trp

## Summary

**BCO2 p.Arg487Trp (c.1459C>T)** is classified **Uncertain significance** in BCO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely benign (0.1404); Ultra-rare (popmax 0.025%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs774937117 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.025%, amr)

## For patients & families {#patients}

This is a change in the BCO2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [BCO2](https://sugi.bio/atlas/gene/BCO2/) |
| Protein change (HGVS p.) | p.Arg487Trp |
| Coding change (HGVS c.) | c.1459C>T |
| MANE Select transcript | [NM_031938](https://www.ncbi.nlm.nih.gov/nuccore/NM_031938) |
| dbSNP | [rs774937117](https://www.ncbi.nlm.nih.gov/snp/rs774937117/) |
| Variant type | single nucleotide variant |
| Location | chr11:112214888-112214888 (GRCh38) |
| ClinVar | [VCV3133533](https://www.ncbi.nlm.nih.gov/clinvar/variation/3133533/) |

**All HGVS expressions:** `NC_000011.10:g.112214888C>T`, `NC_000011.9:g.112085611C>T`, `NM_001037290.4:c.1357C>T`, `NM_001256397.3:c.1357C>T`, `NM_001256398.3:c.1240C>T`, `NM_001256400.3:c.1144C>T`, `NM_031938.7:c.1459C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1404)
- REVEL 0.734 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -10.23 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 2.196, GERP 1.82, phastCons 0.998 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 31.0**. 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 0.97** across the covering region of the MANE Select transcript (112,175,602–112,217,871), spanning 42,269 bp. Chi-square p 0.37. 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 (C>G, Δ0.24 donor gain), 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 **0.025%** (amr) · FAF95 0.0154% · FAF99 0.0124% · 15/60,004 in the highest group · 65/1,613,994 alleles overall — ultra-rare (popmax 0.025%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.025% | 4,000 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,621 |
| Finnish (not grpmax-eligible) | 0.00469% | 21,343 |
| South Asian | 0.00439% | 22,770 |
| European (non-Finnish) | 0.00314% | 31,892 |
| African / African-American | 0.00267% | 37,450 |

*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}

**BCO2** population constraint: LOEUF 1.047, pLI 8.0386e-13, missense-Z 0.59178. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.41, 78% of residues very-high.

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

*Describes the biological roles of BCO2 (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:** BCO2's established molecular role includes oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen.


### Pathways affected {#pathways}

BCO2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Retinoid metabolism and transport](https://reactome.org/content/detail/R-HSA-975634) | curated |

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

**Molecular function:** oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen.

**Biological process:** carotene metabolic process, carotene catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-11.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-11 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related BCO2 variant pages (same residue, condition, or type): [BCO2 p.Arg472Ter](/variant/bco2-p-arg472ter), [BCO2 p.Ala115Val](/variant/bco2-p-ala115val), [BCO2 p.Ala223Gly](/variant/bco2-p-ala223gly), [BCO2 p.Ala318Val](/variant/bco2-p-ala318val), [BCO2 p.Ala437Ser](/variant/bco2-p-ala437ser), [BCO2 p.Arg184Trp](/variant/bco2-p-arg184trp), [BCO2 p.Arg253Gln](/variant/bco2-p-arg253gln), [BCO2 p.Arg27Trp](/variant/bco2-p-arg27trp).

### 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 3133533). 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.*