# NM_003571.4(BFSP2):c.166del (p.Val56fs)

https://sugi.bio/variant/bfsp2-p-val56fs

## Summary

**BFSP2 p.Val56fs (c.166del)** is classified **Pathogenic** in BFSP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-06). No gnomAD frequency available for this variant; Associated with cataract 12 multiple types.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1576552712 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the BFSP2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to cataract 12 multiple types.

*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 | [BFSP2](https://sugi.bio/atlas/gene/BFSP2/) |
| Protein change (HGVS p.) | p.Val56fs |
| Coding change (HGVS c.) | c.166del |
| MANE Select transcript | [NM_003571](https://www.ncbi.nlm.nih.gov/nuccore/NM_003571) |
| dbSNP | [rs1576552712](https://www.ncbi.nlm.nih.gov/snp/rs1576552712/) |
| Variant type | Deletion |
| Location | chr3:133400246-133400246 (GRCh38) |
| ClinVar | [VCV646545](https://www.ncbi.nlm.nih.gov/clinvar/variation/646545/) |

**All HGVS expressions:** `NC_000003.11:g.133119093del`, `NC_000003.12:g.133400249del`, `NG_012425.1:g.5304del`, `NM_003571.4:c.166del`

## 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 -1.979, GERP -3.62 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.067, pLI 1.5672e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 7**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**BFSP2** population constraint: LOEUF 1.067, pLI 1.5672e-11, missense-Z 0.602. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **56** lies in the 'head' region.

AlphaFold model confidence (whole protein): pLDDT 78.15, 59% of residues very-high.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-06.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-09-06 |

## Associated conditions {#conditions}

[cataract 12 multiple types](https://sugi.bio/atlas/disease/cataract-12-multiple-types/).

**Reported phenotype names (ClinVar):** Cataract 12 multiple types.

## Similar variants {#similar}

Related BFSP2 variant pages (same residue, condition, or type): [BFSP2 p.Glu233del](/variant/bfsp2-p-glu233del), [BFSP2 p.Arg4Lys](/variant/bfsp2-p-arg4lys), [BFSP2 p.Arg5Ter](/variant/bfsp2-p-arg5ter), [BFSP2 p.Arg72His](/variant/bfsp2-p-arg72his), [BFSP2 p.Glu141Ala](/variant/bfsp2-p-glu141ala), [BFSP2 p.Glu289Asp](/variant/bfsp2-p-glu289asp), [BFSP2 p.Leu153Gln](/variant/bfsp2-p-leu153gln), [BFSP2 c.572+160A>G](/variant/bfsp2-c-572-plus-160a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 646545). 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.*