# NM_031885.5(BBS2):c.647G>C (p.Arg216Pro)

https://sugi.bio/variant/bbs2-p-arg216pro

## Summary

**BBS2 p.Arg216Pro (c.647G>C)** is classified **Likely pathogenic** in BBS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-19). AlphaMissense: likely pathogenic (0.9438); Very rare (popmax 0.000593%, nfe); Associated with BBS2-related disorder.

**At a glance:** Likely pathogenic · review: Multiple submitters · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.000593%, nfe)

## For patients & families {#patients}

This is a change in the BBS2 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to BBS2-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 | [BBS2](https://sugi.bio/atlas/gene/BBS2/) |
| Protein change (HGVS p.) | p.Arg216Pro |
| Coding change (HGVS c.) | c.647G>C |
| MANE Select transcript | [NM_031885](https://www.ncbi.nlm.nih.gov/nuccore/NM_031885) |
| Variant type | single nucleotide variant |
| Location | chr16:56506190-56506190 (GRCh38) |
| ClinVar | [VCV4816293](https://www.ncbi.nlm.nih.gov/clinvar/variation/4816293/) |

**All HGVS expressions:** `NC_000016.10:g.56506190C>G`, `NC_000016.9:g.56540102C>G`, `NG_009312.2:g.18835G>C`, `NM_001377456.1:c.647G>C`, `NM_031885.5:c.647G>C`, `NR_165293.1:n.809G>C`, `NR_165294.1:n.809G>C`, `NR_165295.1:n.809G>C`, `NR_165296.1:n.809G>C`, `NR_165297.1:n.809G>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9438) — concordant with the pathogenic call
- REVEL 0.533 (indeterminate)
- SaProt LLR -18.763 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 4.902, GERP 1.89, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 9%** most-pathogenic-predicted substitutions in BBS2 (of 4,272 modeled).
- CADD: **PHRED 27.7**. 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 0.87** across the covering region of the MANE Select transcript (56,484,764–56,519,862), spanning 35,098 bp. Chi-square p 9.6e-05. 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 (C>A, Δ0.26 acceptor loss), 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.*
- Pangolin: Δ**0.25** (loss), gain 0.01 / loss 0.25. SpliceAI below 0.2. 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 **0.000593%** (nfe) · FAF95 0.000247% · FAF99 0.000159% · 7/1,179,914 in the highest group · 7/1,461,666 alleles overall — very rare (popmax 0.000593%, nfe).

*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}

**BBS2** population constraint: LOEUF 0.892, pLI 6.2071e-15, missense-Z 1.9805. *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):

- **BBS2-related ciliopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.49, 68% of residues very-high.

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

*Describes the biological roles of BBS2 (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:** BBS2's established molecular role includes RNA polymerase II-specific DNA-binding transcription factor binding.


### Pathways affected {#pathways}

BBS2 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}

**Molecular function:** RNA polymerase II-specific DNA-binding transcription factor binding.

**Biological process:** visual perception, Golgi to plasma membrane protein transport.

## Clinical significance {#significance}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-19.

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

**Submission history:** 2 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-12-19 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-11-26 |

## Associated conditions {#conditions}

[BBS2-related disorder](https://sugi.bio/atlas/disease/bbs2-related-disorder/), [Bardet-Biedl syndrome 2](https://sugi.bio/atlas/disease/bardet-biedl-syndrome-2/).

**Reported phenotype names (ClinVar):** BBS2-related disorder, Bardet-Biedl syndrome 2, BBS2-related condition, BBS2-related disorders.

## Same-residue context {#hotspot}

Residue **216** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BBS2 p.Arg216Ter](/variant/bbs2-p-arg216ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BBS2 variant pages (same residue, condition, or type): [BBS2 p.Arg216Ter](/variant/bbs2-p-arg216ter), [BBS2 p.Arg216Gln](/variant/bbs2-p-arg216gln), [BBS2 c.118-1G>T](/variant/bbs2-c-118-minus-1g-t), [BBS2 c.118-2A>C](/variant/bbs2-c-118-minus-2a-c), [BBS2 c.118-2A>G](/variant/bbs2-c-118-minus-2a-g), [BBS2 c.1225+2T>C](/variant/bbs2-c-1225-plus-2t-c), [BBS2 c.1225+2T>G](/variant/bbs2-c-1225-plus-2t-g), [BBS2 c.1397+1G>A](/variant/bbs2-c-1397-plus-1g-a).

### 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 4816293). 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.*