# NM_001711.6(BGN):c.540C>T (p.Ser180=)

https://sugi.bio/variant/bgn-p-ser180

## Summary

**BGN p.Ser180= (c.540C>T)** is classified **Benign** in BGN (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 48.4%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Meester-Loeys syndrome.

**At a glance:** Benign · review: Multiple submitters · rsID rs1126499 · 8 submitters · 2 linked conditions · common (popmax 48.4%, nfe) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the BGN gene that is classified as benign — not considered disease-causing, submitted by 8 submitters, and is linked to Meester-Loeys syndrome.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024735/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BGN](https://sugi.bio/atlas/gene/BGN/) |
| Protein change (HGVS p.) | p.Ser180= |
| Coding change (HGVS c.) | c.540C>T |
| MANE Select transcript | [NM_001711](https://www.ncbi.nlm.nih.gov/nuccore/NM_001711) |
| dbSNP | [rs1126499](https://www.ncbi.nlm.nih.gov/snp/rs1126499/) |
| Variant type | single nucleotide variant |
| Location | chrX:153506051-153506051 (GRCh38) |
| ClinVar | [VCV1166521](https://www.ncbi.nlm.nih.gov/clinvar/variation/1166521/) |

**All HGVS expressions:** `NC_000023.10:g.152771509C>T`, `NC_000023.11:g.153506051C>T`, `NG_015961.1:g.16099C>T`, `NM_001711.4:c.540C>T`, `NM_001711.5:c.540C>T`, `NM_001711.6:c.540C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 48.4%, nfe) — too common for a highly-penetrant pathogenic allele.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -12.554, GERP -3.8 — fast-evolving / accelerated position
- CADD: **PHRED 1.026**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.28 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 **48.4%** (nfe) · FAF95 48.3% · FAF99 48.3% · 433,333/894,415 in the highest group · 548,673/1,208,518 alleles overall — common (popmax 48.4%, nfe) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 48.4% | 2 |
| Finnish (not grpmax-eligible) | 46% | 2 |
| Middle Eastern | 44.1% | 2 |
| Remaining individuals (not grpmax-eligible) | 44% | 2 |
| South Asian | 40.9% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 39.4% | 3 |
| East Asian | 39.1% | 3 |
| Admixed American | 38% | 3 |
| Amish (not grpmax-eligible) | 35.8% | 3 |
| African / African-American | 15% | 7 |

*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}


Curated gene–disease validity (ClinGen):

- **Meester-Loeys syndrome** — Strong (XL)
- **familial thoracic aortic aneurysm and aortic dissection** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 85.72, 78% of residues very-high.

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

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

**Disease mechanism (Reactome):** BGN 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}

BGN participates in **11 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 |
| [Glycosaminoglycan-protein linkage region biosynthesis](https://reactome.org/content/detail/R-HSA-1971475) | curated |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | electronic |

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (9/9 Benign).

**Submission history:** 9 submissions (2018–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-09-06 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2023-04-04 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2018-12-04 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-14 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2023-01-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-28 |

## Associated conditions {#conditions}

[Meester-Loeys syndrome](https://sugi.bio/atlas/disease/meester-loeys-syndrome/), [X-linked spondyloepimetaphyseal dysplasia](https://sugi.bio/atlas/disease/x-linked-spondyloepimetaphyseal-dysplasia/).

**Reported phenotype names (ClinVar):** Meester-Loeys syndrome, not provided, X-linked spondyloepimetaphyseal dysplasia, Cardiovascular phenotype, not specified, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related BGN variant pages (same residue, condition, or type): [BGN p.Ser180Gly](/variant/bgn-p-ser180gly), [BGN c.770+1G>A](/variant/bgn-c-770-plus-1g-a), [BGN p.Gln75Ter](/variant/bgn-p-gln75ter), [BGN p.Trp25Ter](/variant/bgn-p-trp25ter), [BGN p.Arg214Cys](/variant/bgn-p-arg214cys), [BGN p.Arg6His](/variant/bgn-p-arg6his), [BGN p.Gly66Ser](/variant/bgn-p-gly66ser), [BGN p.Met62Thr](/variant/bgn-p-met62thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1166521). 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.*