# NM_176824.3(BBS7):c.1761G>A (p.Arg587=)

https://sugi.bio/variant/bbs7-p-arg587

## Summary

**BBS7 p.Arg587= (c.1761G>A)** is classified **Likely benign** in BBS7 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-06-16). Very rare (popmax 0.0011%, sas); Associated with BBS7-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · 1 submitter · 1 linked condition · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the BBS7 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to BBS7-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 | [BBS7](https://sugi.bio/atlas/gene/BBS7/) |
| Protein change (HGVS p.) | p.Arg587= |
| Coding change (HGVS c.) | c.1761G>A |
| MANE Select transcript | [NM_176824](https://www.ncbi.nlm.nih.gov/nuccore/NM_176824) |
| Variant type | single nucleotide variant |
| Location | chr4:121828644-121828644 (GRCh38) |
| ClinVar | [VCV3356358](https://www.ncbi.nlm.nih.gov/clinvar/variation/3356358/) |

**All HGVS expressions:** `NC_000004.11:g.122749799C>T`, `NC_000004.12:g.121828644C>T`, `NG_009111.1:g.46844G>A`, `NG_052974.1:g.358G>A`, `NG_052974.2:g.239G>A`, `NM_018190.4:c.1761G>A`, `NM_176824.3:c.1761G>A`

## 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 1.114, GERP 1.01, phastCons 1 — weakly conserved position
- CADD: **PHRED 9.752**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.43 donor 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.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/90,692 in the highest group · 4/1,606,392 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 90,692 |
| European (non-Finnish) | 0.000256% | 391,236 |

*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}

**BBS7** population constraint: LOEUF 0.701, pLI 8.5502e-07, missense-Z 1.7963; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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):

- **BBS7-related ciliopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.99, 84% of residues very-high.

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

*Describes the biological roles of BBS7 (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:** BBS7's established molecular role includes RNA polymerase II-specific DNA-binding transcription factor binding.


### Pathways affected {#pathways}

BBS7 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:** RNA polymerase II-specific DNA-binding transcription factor binding.

**Biological process:** regulation of transcription by RNA polymerase II, positive regulation of proteasomal ubiquitin-dependent protein catabolic process.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2023-06-16.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2023-06-16 |

## Associated conditions {#conditions}

[BBS7-related disorder](https://sugi.bio/atlas/disease/bbs7-related-disorder/).

**Reported phenotype names (ClinVar):** BBS7-related disorder, BBS7-related condition.

## Same-residue context {#hotspot}

Residue **587** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BBS7 p.Arg587fs](/variant/bbs7-p-arg587fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BBS7 variant pages (same residue, condition, or type): [BBS7 c.529-2A>G](/variant/bbs7-c-529-minus-2a-g), [BBS7 p.His323Arg](/variant/bbs7-p-his323arg), [BBS7 p.Thr211Ile](/variant/bbs7-p-thr211ile), [BBS7 p.Ser395Asn](/variant/bbs7-p-ser395asn), [BBS7 c.601+1G>A](/variant/bbs7-c-601-plus-1g-a), [BBS7 p.Arg587fs](/variant/bbs7-p-arg587fs), [BBS7 p.Ile249Asn](/variant/bbs7-p-ile249asn), [BBS7 p.Trp313Ter](/variant/bbs7-p-trp313ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 3356358). 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.*