# NM_176824.3(BBS7):c.1336C>T (p.Arg446Trp)

https://sugi.bio/variant/bbs7-p-arg446trp

## Summary

**BBS7 p.Arg446Trp (c.1336C>T)** is classified **Uncertain significance** in BBS7 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-02-11). AlphaMissense: likely pathogenic (0.8022); Very rare (popmax 0.00446%, eas); Associated with Bardet-Biedl syndrome 7.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs768987725 · 4 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the BBS7 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 7.

*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) |
| Diagnostic panels | BBS7 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/0010206/index) · [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.Arg446Trp |
| Coding change (HGVS c.) | c.1336C>T |
| MANE Select transcript | [NM_176824](https://www.ncbi.nlm.nih.gov/nuccore/NM_176824) |
| dbSNP | [rs768987725](https://www.ncbi.nlm.nih.gov/snp/rs768987725/) |
| Variant type | single nucleotide variant |
| Location | chr4:121839666-121839666 (GRCh38) |
| ClinVar | [VCV1393456](https://www.ncbi.nlm.nih.gov/clinvar/variation/1393456/) |

**All HGVS expressions:** `NC_000004.11:g.122760821G>A`, `NC_000004.12:g.121839666G>A`, `NG_009111.1:g.35822C>T`, `NM_018190.4:c.1336C>T`, `NM_176824.2:c.1336C>T`, `NM_176824.3:c.1336C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8022)
- REVEL 0.802 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.283 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.668, GERP 1.82, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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 0.87** across the covering region of the MANE Select transcript (121,825,863–121,870,313), spanning 44,450 bp. Chi-square p 0.00015. 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 (G>T, Δ0.80 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 (gnomAD v4.1): grpmax **0.00446%** (eas) · FAF95 0.00188% · FAF99 0.00164% · 2/44,866 in the highest group · 43/1,613,562 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,494 |
| East Asian (grpmax) | 0.00446% | 22,433 |
| African / African-American | 0.00401% | 24,959 |
| European (non-Finnish) | 0.00263% | 38,055 |
| Admixed American | 0.00167% | 59,966 |
| South Asian | 0.0011% | 91,070 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 30, triplosensitivity Not yet evaluated (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):

- **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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-02-11.

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

**Submission history:** 4 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-24 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-07-23 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-11 |

## Associated conditions {#conditions}

[Bardet-Biedl syndrome 7](https://sugi.bio/atlas/disease/bardet-biedl-syndrome-7/), [Bardet-Biedl syndrome](https://sugi.bio/atlas/disease/bardet-biedl-syndrome/).

**Reported phenotype names (ClinVar):** Bardet-Biedl syndrome 7, Bardet-Biedl syndrome, BBS7-related disorder, not provided, BBS7-related condition, none provided.

## Similar variants {#similar}

Related BBS7 variant pages (same residue, condition, or type): [BBS7 p.Arg446Gln](/variant/bbs7-p-arg446gln), [BBS7 c.1305+2T>A](/variant/bbs7-c-1305-plus-2t-a), [BBS7 c.1371+1G>A](/variant/bbs7-c-1371-plus-1g-a), [BBS7 c.1512-1G>A](/variant/bbs7-c-1512-minus-1g-a), [BBS7 c.1677-2A>G](/variant/bbs7-c-1677-minus-2a-g), [BBS7 c.1891-2A>C](/variant/bbs7-c-1891-minus-2a-c), [BBS7 c.342-2A>G](/variant/bbs7-c-342-minus-2a-g), [BBS7 c.529-2A>G](/variant/bbs7-c-529-minus-2a-g).

### 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 1393456). 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.*