# NM_031938.7(BCO2):c.1415G>A (p.Arg472Gln)

https://sugi.bio/variant/bco2-p-arg472gln

## Summary

**BCO2 p.Arg472Gln (c.1415G>A)** is classified **Likely benign** in BCO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-08). AlphaMissense: likely benign (0.0694); Very rare (popmax 0.00533%, afr).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00533%, afr)

## For patients & families {#patients}

This is a change in the BCO2 gene that is classified as likely benign — not considered disease-causing, 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.Arg472Gln |
| Coding change (HGVS c.) | c.1415G>A |
| MANE Select transcript | [NM_031938](https://www.ncbi.nlm.nih.gov/nuccore/NM_031938) |
| Variant type | single nucleotide variant |
| Location | chr11:112214844-112214844 (GRCh38) |
| ClinVar | [VCV3824034](https://www.ncbi.nlm.nih.gov/clinvar/variation/3824034/) |

**All HGVS expressions:** `NC_000011.10:g.112214844G>A`, `NC_000011.9:g.112085567G>A`, `NM_001037290.4:c.1313G>A`, `NM_001256397.3:c.1313G>A`, `NM_001256398.3:c.1196G>A`, `NM_001256400.3:c.1100G>A`, `NM_031938.7:c.1415G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0694)
- REVEL 0.231 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.048 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 3.077, GERP -1.8, phastCons 0.373 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 10.27**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 15 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00533%** (afr) · FAF95 0.0018% · FAF99 0.00156% · 4/75,046 in the highest group · 37/1,614,028 alleles overall — very rare (popmax 0.00533%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00533% | 18,762 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,254 |
| European (non-Finnish) | 0.00254% | 39,330 |
| Admixed American | 0.00167% | 60,024 |

*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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-08.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-01-08 |

**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 2026-10-14); 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 2026-10-14); 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 3824034). 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.*