# NM_001195.5(BFSP1):c.1029A>G (p.Gly343=)

https://sugi.bio/variant/bfsp1-p-gly343

## Summary

**BFSP1 p.Gly343= (c.1029A>G)** is classified **Uncertain significance** in BFSP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-10). No allele count reported in gnomAD v4.1 (AN 1,541,246); Associated with cataract 33.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2515062275 · 1 submitter · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 1,541,246)

## For patients & families {#patients}

This is a change in the BFSP1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to cataract 33.

*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.*

|  |  |
| --- | --- |
| Diagnostic panels | BFSP1 is a diagnostic-grade gene on 1 Genomics England panel |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018236/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BFSP1](https://sugi.bio/atlas/gene/BFSP1/) |
| Protein change (HGVS p.) | p.Gly343= |
| Coding change (HGVS c.) | c.1029A>G |
| MANE Select transcript | [NM_001195](https://www.ncbi.nlm.nih.gov/nuccore/NM_001195) |
| dbSNP | [rs2515062275](https://www.ncbi.nlm.nih.gov/snp/rs2515062275/) |
| Variant type | single nucleotide variant |
| Location | chr20:17496951-17496951 (GRCh38) |
| ClinVar | [VCV2128124](https://www.ncbi.nlm.nih.gov/clinvar/variation/2128124/) |

**All HGVS expressions:** `NC_000020.10:g.17477596T>C`, `NC_000020.11:g.17496951T>C`, `NG_012423.2:g.77270A>G`, `NM_001161705.2:c.654A>G`, `NM_001195.5:c.1029A>G`, `NM_001278606.2:c.612A>G`, `NM_001278607.2:c.696A>G`, `NM_001278608.2:c.612A>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.30) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -1.037, GERP -3.97 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.505**. 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 deltas (raw): acceptor loss **0.04**, donor loss **0.30**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.04**, donor loss **0.30**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.27** (loss), gain 0.01 / loss 0.27. 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: **no allele count reported in gnomAD v4.1 (AN 1,541,246)** — 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}

**BFSP1** population constraint: LOEUF 1.371, pLI 7.9397e-15, missense-Z -0.76131. *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 **343** lies in the 'tail' region.

AlphaFold model confidence (whole protein): pLDDT 64.66, 36% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-10.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-10 |

## Associated conditions {#conditions}

[cataract 33](https://sugi.bio/atlas/disease/cataract-33/).

**Reported phenotype names (ClinVar):** Cataract 33, CATARACT 33, CORTICAL.

## Similar variants {#similar}

Related BFSP1 variant pages (same residue, condition, or type): [BFSP1 p.Ala643Thr](/variant/bfsp1-p-ala643thr), [BFSP1 p.Arg560Cys](/variant/bfsp1-p-arg560cys), [BFSP1 p.Arg69Trp](/variant/bfsp1-p-arg69trp), [BFSP1 p.Asp19Asn](/variant/bfsp1-p-asp19asn), [BFSP1 p.Gln294Arg](/variant/bfsp1-p-gln294arg), [BFSP1 p.Gly46Trp](/variant/bfsp1-p-gly46trp), [BFSP1 p.Ile271Thr](/variant/bfsp1-p-ile271thr), [BFSP1 p.Leu68Phe](/variant/bfsp1-p-leu68phe).

### 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 2128124). 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.*