# NM_001122955.4(BSCL2):c.992G>A (p.Arg331His)

https://sugi.bio/variant/bscl2-p-arg331his

## Summary

**BSCL2 p.Arg331His (c.992G>A)** is classified **Conflicting classifications of pathogenicity** in BSCL2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-17). AlphaMissense: likely benign (0.0761); Ultra-rare (popmax 0.0507%, afr); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs201229787 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0507%, afr)

## 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 3 submitters, and is linked to Inborn genetic diseases.

*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 | [BSCL2](https://sugi.bio/atlas/gene/BSCL2/) |
| Protein change (HGVS p.) | p.Arg331His |
| Coding change (HGVS c.) | c.992G>A |
| MANE Select transcript | [NM_001122955](https://www.ncbi.nlm.nih.gov/nuccore/NM_001122955) |
| dbSNP | [rs201229787](https://www.ncbi.nlm.nih.gov/snp/rs201229787/) |
| Variant type | single nucleotide variant |
| Location | chr11:62691293-62691293 (GRCh38) |
| ClinVar | [VCV576407](https://www.ncbi.nlm.nih.gov/clinvar/variation/576407/) |

**All HGVS expressions:** `LRG_235:g.23282G>A`, `LRG_235t2:c.800G>A`, `NC_000011.10:g.62691293C>T`, `NC_000011.9:g.62458765C>T`, `NG_008461.1:g.23282G>A`, `NG_033077.1:g.3607G>A`, `NM_001122955.4:c.992G>A`, `NM_001130702.2:c.672-152G>A`, `NM_001386027.1:c.992G>A`, `NM_001386028.1:c.992G>A`, `NM_032667.6:c.800G>A`, `NR_037946.1:n.3512G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0761)
- REVEL 0.34 (indeterminate)
- SaProt LLR -7.039 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 0.826, GERP 0.21, phastCons 0.999 — weakly conserved position
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R267H** vs ClinVar **R331H**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 23.5**. 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 1.03** across the covering region of the MANE Select transcript (62,690,370–62,692,417), spanning 2,047 bp. Chi-square p 0.6. 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>G, Δ0.20 donor loss), 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 **0.0507%** (afr) · FAF95 0.0379% · FAF99 0.0334% · 38/75,022 in the highest group · 54/1,614,130 alleles overall — ultra-rare (popmax 0.0507%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0507% | 1,974 |
| Middle Eastern | 0.0165% | 6,062 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,501 |
| Admixed American | 0.00167% | 60,012 |
| South Asian | 0.0011% | 91,080 |
| European (non-Finnish) | 0.000678% | 147,502 |

*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 **331** 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.Arg331His 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 2025-12-17.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely benign).

**Submission history:** 3 submissions (2020–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-03-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-17 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-05 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [Charcot-Marie-Tooth disease type 2](https://sugi.bio/atlas/disease/charcot-marie-tooth-disease-type-2/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Charcot-Marie-Tooth disease type 2, not provided, Charcot-Marie-Tooth type 2, none provided.

## Similar variants {#similar}

Related BSCL2 variant pages (same residue, condition, or type): [BSCL2 p.Arg331Cys](/variant/bscl2-p-arg331cys), [BSCL2 c.1006-2A>C](/variant/bscl2-c-1006-minus-2a-c), [BSCL2 c.486+1G>A](/variant/bscl2-c-486-plus-1g-a), [BSCL2 p.Ala276Pro](/variant/bscl2-p-ala276pro), [BSCL2 p.Arg329Ter](/variant/bscl2-p-arg329ter), [BSCL2 p.Asn152Ser](/variant/bscl2-p-asn152ser), [BSCL2 p.Glu253Ter](/variant/bscl2-p-glu253ter), [BSCL2 p.Ser154Leu](/variant/bscl2-p-ser154leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 576407). 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.*