# NM_017429.3(BCO1):c.51G>T (p.Arg17Ser)

https://sugi.bio/variant/bco1-p-arg17ser

## Summary

**BCO1 p.Arg17Ser (c.51G>T)** is classified **Uncertain significance** in BCO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.2005); Very rare (popmax 0.00267%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the BCO1 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 | [BCO1](https://sugi.bio/atlas/gene/BCO1/) |
| Protein change (HGVS p.) | p.Arg17Ser |
| Coding change (HGVS c.) | c.51G>T |
| MANE Select transcript | [NM_017429](https://www.ncbi.nlm.nih.gov/nuccore/NM_017429) |
| Variant type | single nucleotide variant |
| Location | chr16:81238959-81238959 (GRCh38) |
| ClinVar | [VCV3991116](https://www.ncbi.nlm.nih.gov/clinvar/variation/3991116/) |

**All HGVS expressions:** `NC_000016.10:g.81238959G>T`, `NC_000016.9:g.81272564G>T`, `NG_012171.1:g.5269G>T`, `NM_017429.3:c.51G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2005)
- REVEL 0.16 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.247 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.399, GERP -2.75, phastCons 0.819 — weakly conserved position
- CADD: **PHRED 16.66**. 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 1.16** across the covering region of the MANE Select transcript (81,238,909–81,290,574), spanning 51,665 bp. Chi-square p 2.8e-05. 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 **0.01**, acceptor gain **0.00**, donor gain **0.22**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.22**.
- Population frequency (gnomAD v4.1): grpmax **0.00267%** (afr) · FAF95 0.000443% · FAF99 0.000166% · 2/74,886 in the highest group · 4/1,613,776 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00267% | 37,443 |
| European (non-Finnish) | 0.00017% | 589,946 |

*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}

**BCO1** population constraint: LOEUF 1.17, pLI 1.2604e-16, missense-Z -1.0043. *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 90.03, 77% of residues very-high.

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

*Describes the biological roles of BCO1 (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:** BCO1's established molecular role includes beta-carotene 15,15'-dioxygenase activity.


### Pathways affected {#pathways}

BCO1 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:** beta-carotene 15,15'-dioxygenase activity.

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

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-03.

**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 | 2025-04-03 |

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

## Similar variants {#similar}

Related BCO1 variant pages (same residue, condition, or type): [BCO1 p.Arg266Trp](/variant/bco1-p-arg266trp), [BCO1 p.Thr170Met](/variant/bco1-p-thr170met), [BCO1 c.1101+48C>T](/variant/bco1-c-1101-plus-48c-t), [BCO1 c.1102-81T>C](/variant/bco1-c-1102-minus-81t-c), [BCO1 c.1303-13G>A](/variant/bco1-c-1303-minus-13g-a), [BCO1 c.1303-70A>G](/variant/bco1-c-1303-minus-70a-g), [BCO1 c.194-219A>G](/variant/bco1-c-194-minus-219a-g), [BCO1 c.194-74A>G](/variant/bco1-c-194-minus-74a-g).

### 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 3991116). 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.*