# NM_152618.3(BBS12):c.1151del (p.Ser384fs)

https://sugi.bio/variant/bbs12-p-ser384fs

## Summary

**BBS12 p.Ser384fs (c.1151del)** is classified **Pathogenic/Likely pathogenic** in BBS12 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-11-04). Very rare (popmax 0.00267%, afr); Associated with BBS12-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1553941404 · 7 submitters · 3 linked conditions · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the BBS12 gene that is considered likely disease-causing, submitted by 7 submitters, and is linked to BBS12-related disorder.

*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 | [BBS12](https://sugi.bio/atlas/gene/BBS12/) |
| Protein change (HGVS p.) | p.Ser384fs |
| Coding change (HGVS c.) | c.1151del |
| MANE Select transcript | [NM_152618](https://www.ncbi.nlm.nih.gov/nuccore/NM_152618) |
| dbSNP | [rs1553941404](https://www.ncbi.nlm.nih.gov/snp/rs1553941404/) |
| Variant type | Deletion |
| Location | chr4:122743043-122743043 (GRCh38) |
| ClinVar | [VCV550386](https://www.ncbi.nlm.nih.gov/clinvar/variation/550386/) |

**All HGVS expressions:** `NC_000004.11:g.123664198del`, `NC_000004.12:g.122743043del`, `NG_021203.1:g.15342del`, `NM_001178007.2:c.1151del`, `NM_152618.2:c.1151del`, `NM_152618.3:c.1151del`

## 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 0.519, GERP -0.501 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.419, pLI 0.0035062. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (2 of 2)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 21.1**. 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** — 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 (gnomAD v4.1): grpmax **0.00267%** (afr) · FAF95 0.000443% · FAF99 0.000166% · 2/74,958 in the highest group · 4/1,614,152 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00267% | 37,479 |
| Admixed American | 0.00167% | 60,014 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,490 |

*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}

**BBS12** population constraint: LOEUF 1.419, pLI 0.0035062, missense-Z 1.5921. *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):

- **BBS12-related ciliopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 73.92, 47% of residues very-high.

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

*Describes the biological roles of BBS12 (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.*


### Pathways affected {#pathways}

BBS12 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [BBSome-mediated cargo-targeting to cilium](https://reactome.org/content/detail/R-HSA-5620922) | other |

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

**Biological process:** negative regulation of fat cell differentiation, chaperone-mediated protein complex assembly.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-04.

**Submitter consensus:** conflicting (5 Likely pathogenic, 1 Uncertain significance, 1 Pathogenic).

**Submission history:** 7 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Gharavi Laboratory, Columbia University | Uncertain significance | no assertion criteria provided | research | 2018-09-16 |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2017-01-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-08-19 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-09-14 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-11-04 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-08-14 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-08-23 |

## Associated conditions {#conditions}

[BBS12-related disorder](https://sugi.bio/atlas/disease/bbs12-related-disorder/), [Bardet-Biedl syndrome 12](https://sugi.bio/atlas/disease/bardet-biedl-syndrome-12/), [Bardet-Biedl syndrome](https://sugi.bio/atlas/disease/bardet-biedl-syndrome/).

**Reported phenotype names (ClinVar):** BBS12-related disorder, Bardet-Biedl syndrome 12, not provided, Bardet-Biedl syndrome, BBS12-related condition, none provided.

## Similar variants {#similar}

Related BBS12 variant pages (same residue, condition, or type): [BBS12 p.Ser384=](/variant/bbs12-p-ser384), [BBS12 p.Ser384Thr](/variant/bbs12-p-ser384thr), [BBS12 p.Asn485fs](/variant/bbs12-p-asn485fs), [BBS12 p.Asn649_Ser650insTer](/variant/bbs12-p-asn649-ser650inster), [BBS12 p.Asp383fs](/variant/bbs12-p-asp383fs), [BBS12 p.Asp480fs](/variant/bbs12-p-asp480fs), [BBS12 p.Cys140fs](/variant/bbs12-p-cys140fs), [BBS12 p.Cys304fs](/variant/bbs12-p-cys304fs).

### 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 550386). 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.*