# NM_001256447.2(BCAP31):c.361A>T (p.Thr121Ser)

https://sugi.bio/variant/bcap31-p-thr121ser

## Summary

**BCAP31 p.Thr121Ser (c.361A>T)** is classified **Likely benign** in BCAP31 (ClinVar, No assertion criteria, 2 submitters). AlphaMissense: likely benign (0.1484); Very rare (popmax 0.00218%, amr).

**At a glance:** Likely benign · review: No assertion criteria · rsID rs782125326 · 2 submitters · AlphaMissense likely benign · very rare (popmax 0.00218%, amr)

## For patients & families {#patients}

This is a change in the BCAP31 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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 | [BCAP31](https://sugi.bio/atlas/gene/BCAP31/) |
| Protein change (HGVS p.) | p.Thr121Ser |
| Coding change (HGVS c.) | c.361A>T |
| MANE Select transcript | [NM_001256447](https://www.ncbi.nlm.nih.gov/nuccore/NM_001256447) |
| dbSNP | [rs782125326](https://www.ncbi.nlm.nih.gov/snp/rs782125326/) |
| Variant type | single nucleotide variant |
| Location | chrX:153704075-153704075 (GRCh38) |
| ClinVar | [VCV1206221](https://www.ncbi.nlm.nih.gov/clinvar/variation/1206221/) |

**All HGVS expressions:** `NC_000023.10:g.152969530T>A`, `NC_000023.11:g.153704075T>A`, `NG_023231.1:g.25672A>T`, `NM_001139441.1:c.361A>T`, `NM_001139457.2:c.562A>T`, `NM_001256447.2:c.361A>T`, `NM_005745.8:c.361A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1484)
- REVEL 0.123 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.139 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.57) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 6.072, GERP 1.71, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.2**. 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 0.64** across the covering region of the MANE Select transcript (153,700,940–153,723,244), spanning 22,304 bp. Chi-square p 6.9e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.06**, donor loss **0.00**, acceptor gain **0.57**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.06**, donor loss **0.00**, acceptor gain **0.57**, donor gain **0.00**.
- Pangolin: Δ**0.45** (gain), gain 0.45 / loss 0.26. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00218%** (amr) · FAF95 0.00101% · FAF99 0.000798% · 1/45,915 in the highest group · 17/1,096,048 alleles overall — very rare (popmax 0.00218%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00218% | 45,915 |
| Remaining individuals (not grpmax-eligible) | 0.0021% | 47,520 |
| European (non-Finnish) | 0.00168% | 59,628 |

*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}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*.

**Submitter consensus:** unanimous (2/2 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related BCAP31 variant pages (same residue, condition, or type): [BCAP31 p.Arg118Cys](/variant/bcap31-p-arg118cys), [BCAP31 p.Glu245Lys](/variant/bcap31-p-glu245lys), [BCAP31 p.Gly165Arg](/variant/bcap31-p-gly165arg), [BCAP31 p.Gly239Asp](/variant/bcap31-p-gly239asp), [BCAP31 p.Ile56Val](/variant/bcap31-p-ile56val), [BCAP31 p.Leu226Val](/variant/bcap31-p-leu226val), [BCAP31 p.Leu40Pro](/variant/bcap31-p-leu40pro), [BCAP31 p.Lys30Arg](/variant/bcap31-p-lys30arg).

### 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 1206221). 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.*