# NM_001256447.2(BCAP31):c.97C>T (p.Gln33Ter)

https://sugi.bio/variant/bcap31-p-gln33ter

## Summary

**BCAP31 p.Gln33Ter (c.97C>T)** is classified **Pathogenic** in BCAP31 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2013-09-05). Absent from gnomAD v4.1; Associated with severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs397515620 · 2 submitters · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the BCAP31 gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to severe motor and intellectual disabilities-sensorineural deafness-dystonia 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/0017592/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BCAP31](https://sugi.bio/atlas/gene/BCAP31/) |
| Protein change (HGVS p.) | p.Gln33Ter |
| Coding change (HGVS c.) | c.97C>T |
| MANE Select transcript | [NM_001256447](https://www.ncbi.nlm.nih.gov/nuccore/NM_001256447) |
| dbSNP | [rs397515620](https://www.ncbi.nlm.nih.gov/snp/rs397515620/) |
| Variant type | single nucleotide variant |
| Location | chrX:153720968-153720968 (GRCh38) |
| ClinVar | [VCV68446](https://www.ncbi.nlm.nih.gov/clinvar/variation/68446/) |

**All HGVS expressions:** `LRG_1017:g.1101G>A`, `NC_000023.10:g.152986423G>A`, `NC_000023.11:g.153720968G>A`, `NG_009022.2:g.1101G>A`, `NG_023231.1:g.8779C>T`, `NM_001139441.1:c.97C>T`, `NM_001139457.2:c.298C>T`, `NM_001256447.2:c.97C>T`, `NM_005745.8:c.97C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.678, GERP 1.67, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 8**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 37.0**. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**BCAP31** population constraint: ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.74, 51% of residues very-high.

**3 experimental structure(s)** (PDB): [4JZL](https://www.rcsb.org/structure/4JZL), [4JZP](https://www.rcsb.org/structure/4JZP), [8XWX](https://www.rcsb.org/structure/8XWX).

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

*Describes the biological roles of BCAP31 (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:** BCAP31 participates in disease-associated pathways. In Reactome, BCAP31 is annotated in disease pathway(s) including **RSV-host interactions**.

**Disease mechanism (Reactome):** BCAP31 loss or alteration is curated in [RSV-host interactions](https://reactome.org/content/detail/R-HSA-9833110).

### Pathways affected {#pathways}

BCAP31 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [RSV-host interactions](https://reactome.org/content/detail/R-HSA-9833110) | curated |
| [Antigen Presentation: Folding, assembly and peptide loading of class I MHC](https://reactome.org/content/detail/R-HSA-983170) | curated |
| [Apoptotic cleavage of cellular proteins](https://reactome.org/content/detail/R-HSA-111465) | curated |
| [Apoptotic execution phase](https://reactome.org/content/detail/R-HSA-75153) | curated |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |

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

**Biological process:** obsolete protein targeting to mitochondrion, response to endoplasmic reticulum stress, positive regulation of retrograde protein transport, ER to cytosol, positive regulation of ERAD pathway, positive regulation of ubiquitin-dependent protein catabolic process, positive regulation of intrinsic apoptotic signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2013-09-05.

**Submitter consensus:** unanimous (1/1 Pathogenic).

**Submission history:** 2 submissions (2013); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2013-09-05 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

## Associated conditions {#conditions}

[severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome](https://sugi.bio/atlas/disease/severe-motor-and-intellectual-disabilities-sensorineural-deafness-dystonia-syndrome/).

**Reported phenotype names (ClinVar):** Severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome, Thyroid cancer, nonmedullary, 1, Chromosome Xq28 deletion syndrome.

## Similar variants {#similar}

Related BCAP31 variant pages (same residue, condition, or type): [BCAP31 p.Gly239Asp](/variant/bcap31-p-gly239asp), [BCAP31 c.341+2T>G](/variant/bcap31-c-341-plus-2t-g), [BCAP31 p.Gln139Ter](/variant/bcap31-p-gln139ter), [BCAP31 p.Gln156Ter](/variant/bcap31-p-gln156ter), [BCAP31 p.Ala106Val](/variant/bcap31-p-ala106val), [BCAP31 p.Arg31Lys](/variant/bcap31-p-arg31lys), [BCAP31 p.Asp164Glu](/variant/bcap31-p-asp164glu), [BCAP31 p.Val237Leu](/variant/bcap31-p-val237leu).

### 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 68446). 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.*