# NM_031885.5(BBS2):c.1786G>A (p.Val596Met)

https://sugi.bio/variant/bbs2-p-val596met

## Summary

**BBS2 p.Val596Met (c.1786G>A)** is classified **Uncertain significance** in BBS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-06-06). AlphaMissense: likely benign (0.1439); Ultra-rare (popmax 0.0174%, afr); Associated with Bardet-Biedl syndrome 2.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs375828912 · 4 submitters · 3 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0174%, afr)

## For patients & families {#patients}

This is a change in the BBS2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 submitters, and is linked to Bardet-Biedl syndrome 2.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive, Oligogenic |
| Age of onset (of this condition) | Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Specific population) |
| Clinical trials | 18 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | BBS2 is a diagnostic-grade gene on 17 Genomics England panels |

**Commonly reported features of Bardet-Biedl syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Retinal dystrophy — Obligate (100%)
- Cone/cone-rod dystrophy — Very frequent (99-80%)
- Obesity — Very frequent (99-80%)
- Childhood-onset truncal obesity — Very frequent (99-80%)
- Neurodevelopmental delay — Very frequent (99-80%)
- Abnormality of the genitourinary system — Frequent (79-30%)
- Hypogonadism — Frequent (79-30%)
- Abnormal oral cavity morphology — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000821/index) · [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.Val596Met |
| Coding change (HGVS c.) | c.1786G>A |
| MANE Select transcript | [NM_031885](https://www.ncbi.nlm.nih.gov/nuccore/NM_031885) |
| dbSNP | [rs375828912](https://www.ncbi.nlm.nih.gov/snp/rs375828912/) |
| Variant type | single nucleotide variant |
| Location | chr16:56497754-56497754 (GRCh38) |
| ClinVar | [VCV1412652](https://www.ncbi.nlm.nih.gov/clinvar/variation/1412652/) |

**All HGVS expressions:** `NC_000016.10:g.56497754C>T`, `NC_000016.9:g.56531666C>T`, `NG_009312.2:g.27271G>A`, `NM_001377456.1:c.1786G>A`, `NM_031885.3:c.1786G>A`, `NM_031885.5:c.1786G>A`, `NR_165293.1:n.2076G>A`, `NR_165294.1:n.2073G>A`, `NR_165295.1:n.1904G>A`, `NR_165296.1:n.1776G>A`, `NR_165297.1:n.1776G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1439)
- REVEL 0.48 (indeterminate)
- SaProt LLR -9.487 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **donor loss** (Δ 0.38) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.944, GERP 2.06, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.8**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.38**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0174%** (afr) · FAF95 0.0103% · FAF99 0.00813% · 13/74,870 in the highest group · 15/1,613,340 alleles overall — ultra-rare (popmax 0.0174%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0174% | 5,759 |
| Admixed American | 0.00167% | 59,976 |
| European (non-Finnish) | 8.48e-05% | 1,179,857 |

*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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-06-06.

**Submitter consensus:** unanimous (4/4 Uncertain significance).

**Submission history:** 4 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-25 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-01 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-05-12 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-06 |

## Associated conditions {#conditions}

[Bardet-Biedl syndrome 2](https://sugi.bio/atlas/disease/bardet-biedl-syndrome-2/), [retinitis pigmentosa 74](https://sugi.bio/atlas/disease/retinitis-pigmentosa-74/), [Bardet-Biedl syndrome](https://sugi.bio/atlas/disease/bardet-biedl-syndrome/).

**Reported phenotype names (ClinVar):** Bardet-Biedl syndrome 2, Bardet-Biedl syndrome, Inborn genetic diseases, BBS2-related disorder, Retinitis pigmentosa 74, BBS2-related disorders, BBS2-related condition.

## Similar variants {#similar}

Related BBS2 variant pages (same residue, condition, or type): [BBS2 p.Val596Leu](/variant/bbs2-p-val596leu), [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), [BBS2 c.1397+2T>C](/variant/bbs2-c-1397-plus-2t-c).

### 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 1412652). 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.*