# NM_021948.5(BCAN):c.2627C>G (p.Pro876Arg)

https://sugi.bio/variant/bcan-p-pro876arg

## Summary

**BCAN p.Pro876Arg (c.2627C>G)** is classified **Uncertain significance** in BCAN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-02). AlphaMissense: likely benign (0.0843); Ultra-rare (popmax 0.0571%, sas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs539632414 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0571%, sas)

## For patients & families {#patients}

This is a change in the BCAN 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 | [BCAN](https://sugi.bio/atlas/gene/BCAN/) |
| Protein change (HGVS p.) | p.Pro876Arg |
| Coding change (HGVS c.) | c.2627C>G |
| MANE Select transcript | [NM_021948](https://www.ncbi.nlm.nih.gov/nuccore/NM_021948) |
| dbSNP | [rs539632414](https://www.ncbi.nlm.nih.gov/snp/rs539632414/) |
| Variant type | single nucleotide variant |
| Location | chr1:156658732-156658732 (GRCh38) |
| ClinVar | [VCV3133225](https://www.ncbi.nlm.nih.gov/clinvar/variation/3133225/) |

**All HGVS expressions:** `NC_000001.10:g.156628524C>G`, `NC_000001.11:g.156658732C>G`, `NG_030013.1:g.21785C>G`, `NM_021948.5:c.2627C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0843)
- REVEL 0.064 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.479 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.69, GERP 2.03, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.6**. 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 0.95** across the covering region of the MANE Select transcript (156,648,067–156,659,131), spanning 11,064 bp. Chi-square p 0.11. 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>A, 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 **0.0571%** (sas) · FAF95 0.0447% · FAF99 0.0403% · 52/91,086 in the highest group · 71/1,613,932 alleles overall — ultra-rare (popmax 0.0571%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0571% | 1,752 |
| Middle Eastern | 0.033% | 3,031 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,418 |
| European (non-Finnish) | 0.000932% | 107,274 |

*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}

**BCAN** population constraint: LOEUF 0.695, pLI 4.1599e-08, missense-Z 0.79975. *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 70.06, 42% of residues very-high.

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

*Describes the biological roles of BCAN (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:** BCAN participates in disease-associated pathways. In Reactome, BCAN is annotated in disease pathway(s) including **Defective B3GALT6 causes EDSP2 and SEMDJL1**, **Defective B3GAT3 causes JDSSDHD**.

**Disease mechanism (Reactome):** BCAN loss or alteration is curated in [Defective B3GALT6 causes EDSP2 and SEMDJL1](https://reactome.org/content/detail/R-HSA-4420332), [Defective B3GAT3 causes JDSSDHD](https://reactome.org/content/detail/R-HSA-3560801), [Defective B4GALT7 causes EDS, progeroid type](https://reactome.org/content/detail/R-HSA-3560783).

### Pathways affected {#pathways}

BCAN participates in **12 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective B3GALT6 causes EDSP2 and SEMDJL1](https://reactome.org/content/detail/R-HSA-4420332) | curated |
| ⚕ [Defective B3GAT3 causes JDSSDHD](https://reactome.org/content/detail/R-HSA-3560801) | curated |
| ⚕ [Defective B4GALT7 causes EDS, progeroid type](https://reactome.org/content/detail/R-HSA-3560783) | curated |
| ⚕ [Defective CHST14 causes EDS, musculocontractural type](https://reactome.org/content/detail/R-HSA-3595174) | curated |
| ⚕ [Defective CHST3 causes SEDCJD](https://reactome.org/content/detail/R-HSA-3595172) | curated |
| ⚕ [Defective CHSY1 causes TPBS](https://reactome.org/content/detail/R-HSA-3595177) | curated |
| [CS-GAG biosynthesis](https://reactome.org/content/detail/R-HSA-2022870) | curated |
| [CS/DS degradation](https://reactome.org/content/detail/R-HSA-2024101) | curated |
| [DS-GAG biosynthesis](https://reactome.org/content/detail/R-HSA-2022923) | curated |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | curated |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | curated |
| [Glycosaminoglycan-protein linkage region biosynthesis](https://reactome.org/content/detail/R-HSA-1971475) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-02.

**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 | 2023-10-02 |

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

## Similar variants {#similar}

Related BCAN variant pages (same residue, condition, or type): [BCAN p.Arg105Gly](/variant/bcan-p-arg105gly), [BCAN p.Ala10Pro](/variant/bcan-p-ala10pro), [BCAN p.Ala112Thr](/variant/bcan-p-ala112thr), [BCAN p.Ala166Val](/variant/bcan-p-ala166val), [BCAN p.Ala169Thr](/variant/bcan-p-ala169thr), [BCAN p.Ala2Thr](/variant/bcan-p-ala2thr), [BCAN p.Ala357Thr](/variant/bcan-p-ala357thr), [BCAN p.Ala357Val](/variant/bcan-p-ala357val).

### 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 3133225). 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.*