# NM_001122955.4(BSCL2):c.864A>G (p.Arg288=)

https://sugi.bio/variant/bscl2-p-arg288

## Summary

**BSCL2 p.Arg288= (c.864A>G)** is classified **Conflicting classifications of pathogenicity** in BSCL2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-01-01). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary spastic paraplegia 17.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · 2 submitters · 4 linked conditions · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the BSCL2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to hereditary spastic paraplegia 17.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Diagnostic panels | BSCL2 is a diagnostic-grade gene on 17 Genomics England panels |

**Commonly reported features of Autosomal dominant spastic paraplegia type 17** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hyperreflexia — Frequent (79-30%)
- Abnormality of the foot musculature — Frequent (79-30%)
- Spastic gait — Frequent (79-30%)
- Babinski sign — Frequent (79-30%)
- Foot dorsiflexor weakness — Frequent (79-30%)
- Hand muscle atrophy — Frequent (79-30%)
- Split hand — Occasional (29-5%)
- Pes planus — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004219/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BSCL2](https://sugi.bio/atlas/gene/BSCL2/) |
| Protein change (HGVS p.) | p.Arg288= |
| Coding change (HGVS c.) | c.864A>G |
| MANE Select transcript | [NM_001122955](https://www.ncbi.nlm.nih.gov/nuccore/NM_001122955) |
| Variant type | single nucleotide variant |
| Location | chr11:62691421-62691421 (GRCh38) |
| ClinVar | [VCV3599923](https://www.ncbi.nlm.nih.gov/clinvar/variation/3599923/) |

**All HGVS expressions:** `LRG_235:g.23154A>G`, `LRG_235t1:c.864A>G`, `LRG_235t2:c.672A>G`, `NC_000011.10:g.62691421T>C`, `NC_000011.9:g.62458893T>C`, `NG_008461.1:g.23154A>G`, `NG_033077.1:g.3479A>G`, `NM_001122955.4:c.864A>G`, `NM_001130702.2:c.672-280A>G`, `NM_001386027.1:c.864A>G`, `NM_001386028.1:c.864A>G`, `NM_032667.6:c.672A>G`, `NR_037946.1:n.3384A>G`

## Computational & population evidence {#evidence}

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

- **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 4.895, GERP 0.209, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 16.26**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,004 in the highest group · 1/1,614,160 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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}

**BSCL2** population constraint: LOEUF 0.869, pLI 7.4505e-10, missense-Z 1.0354. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **distal hereditary motor neuropathy** — Definitive (AD)
- **lipodystrophy** — Definitive (AR)

## Protein context {#protein}

Residue **288** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 75.09, 46% of residues very-high.

**1 experimental structure(s)** (PDB): [6DS5](https://www.rcsb.org/structure/6DS5).

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

*Describes the biological roles of BSCL2 (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:** BSCL2's established molecular role includes phospholipid binding. p.Arg288= falls in the disordered region.


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

**Molecular function:** phospholipid binding.

**Biological process:** lipid storage, lipid droplet organization, lipid droplet formation.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-01-01.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-11 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-01-01 |

## Associated conditions {#conditions}

[hereditary spastic paraplegia 17](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia-17/), [congenital generalized lipodystrophy type 2](https://sugi.bio/atlas/disease/congenital-generalized-lipodystrophy-type-2/), [severe neurodegenerative syndrome with lipodystrophy](https://sugi.bio/atlas/disease/severe-neurodegenerative-syndrome-with-lipodystrophy/), [neuronopathy, distal hereditary motor, type 5C](https://sugi.bio/atlas/disease/neuronopathy-distal-hereditary-motor-type-5c/).

**Reported phenotype names (ClinVar):** Hereditary spastic paraplegia 17, Congenital generalized lipodystrophy type 2, Neuronopathy, distal hereditary motor, type 5C, Severe neurodegenerative syndrome with lipodystrophy, Inborn genetic diseases, Spastic Paraplegia 17, Autosomal dominant spastic paraplegia type 17, Silver Syndrome, Silver spastic paraplegia syndrome, SPASTIC PARAPLEGIA WITH AMYOTROPHY OF HANDS AND FEET.

## Same-residue context {#hotspot}

Residue **288** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BSCL2 p.Arg288fs](/variant/bscl2-p-arg288fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BSCL2 variant pages (same residue, condition, or type): [BSCL2 p.Arg288fs](/variant/bscl2-p-arg288fs), [BSCL2 c.1006-2A>G](/variant/bscl2-c-1006-minus-2a-g), [BSCL2 c.486+1G>A](/variant/bscl2-c-486-plus-1g-a), [BSCL2 c.631-1G>C](/variant/bscl2-c-631-minus-1g-c), [BSCL2 c.766-2A>G](/variant/bscl2-c-766-minus-2a-g), [BSCL2 p.Ala276Pro](/variant/bscl2-p-ala276pro), [BSCL2 p.Arg202Ter](/variant/bscl2-p-arg202ter), [BSCL2 p.Arg329Ter](/variant/bscl2-p-arg329ter).

### 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 3599923). 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.*