# NM_152384.3(BBS5):c.149T>C (p.Leu50Pro)

https://sugi.bio/variant/bbs5-p-leu50pro

## Summary

**BBS5 p.Leu50Pro (c.149T>C)** is classified **Uncertain significance** in BBS5 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-12). AlphaMissense: likely pathogenic (0.9948); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1683498718 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the BBS5 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [BBS5](https://sugi.bio/atlas/gene/BBS5/) |
| Protein change (HGVS p.) | p.Leu50Pro |
| Coding change (HGVS c.) | c.149T>C |
| MANE Select transcript | [NM_152384](https://www.ncbi.nlm.nih.gov/nuccore/NM_152384) |
| dbSNP | [rs1683498718](https://www.ncbi.nlm.nih.gov/snp/rs1683498718/) |
| Variant type | single nucleotide variant |
| Location | chr2:169487075-169487075 (GRCh38) |
| ClinVar | [VCV1307386](https://www.ncbi.nlm.nih.gov/clinvar/variation/1307386/) |

**All HGVS expressions:** `NC_000002.11:g.170343585T>C`, `NC_000002.12:g.169487075T>C`, `NG_011567.1:g.12580T>C`, `NM_152384.3:c.149T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9948)
- REVEL 0.964 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.679 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.788, GERP 1.57, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 4%** most-pathogenic-predicted substitutions in BBS5 (of 1,992 modeled).
- CADD: **PHRED 32.0**. 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.*
- Regional missense constraint: **o/e 0.89** across the covering region of the MANE Select transcript (169,479,554–169,504,579), spanning 25,025 bp. Chi-square p 0.023. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.20 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- 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}

**BBS5** population constraint: LOEUF 0.884, pLI 0.00025273, missense-Z 1.0111; ClinGen dosage — haploinsufficiency 30, 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):

- **BBS5-related ciliopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.87, 73% of residues very-high.

**1 experimental structure(s)** (PDB): [6XTB](https://www.rcsb.org/structure/6XTB).

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

*Describes the biological roles of BBS5 (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:** BBS5's established molecular role includes phosphatidylinositol-3-phosphate binding.


### Pathways affected {#pathways}

BBS5 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

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

**Molecular function:** phosphatidylinositol-3-phosphate binding, RNA polymerase II-specific DNA-binding transcription factor binding.

**Biological process:** cilium assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-08-12.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-08-12 |

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

## Similar variants {#similar}

Related BBS5 variant pages (same residue, condition, or type): [BBS5 p.Leu50Ile](/variant/bbs5-p-leu50ile), [BBS5 c.143-1G>C](/variant/bbs5-c-143-minus-1g-c), [BBS5 c.209-1G>A](/variant/bbs5-c-209-minus-1g-a), [BBS5 c.209-2A>G](/variant/bbs5-c-209-minus-2a-g), [BBS5 c.522+3A>G](/variant/bbs5-c-522-plus-3a-g), [BBS5 c.681+1G>T](/variant/bbs5-c-681-plus-1g-t), [BBS5 p.Arg138Cys](/variant/bbs5-p-arg138cys), [BBS5 p.Arg138His](/variant/bbs5-p-arg138his).

### 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 1307386). 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.*