# NM_033028.5(BBS4):c.906T>C (p.Phe302=)

https://sugi.bio/variant/bbs4-p-phe302

## Summary

**BBS4 p.Phe302= (c.906T>C)** is classified **Benign** in BBS4 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Bardet-Biedl syndrome.

**At a glance:** Benign · review: Multiple submitters · rsID rs12914333 · 9 submitters · 2 linked conditions · common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the BBS4 gene that is classified as benign — not considered disease-causing, submitted by 9 submitters, and is linked to Bardet-Biedl syndrome.

*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 | BBS4 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/0006866/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BBS4](https://sugi.bio/atlas/gene/BBS4/) |
| Protein change (HGVS p.) | p.Phe302= |
| Coding change (HGVS c.) | c.906T>C |
| MANE Select transcript | [NM_033028](https://www.ncbi.nlm.nih.gov/nuccore/NM_033028) |
| dbSNP | [rs12914333](https://www.ncbi.nlm.nih.gov/snp/rs12914333/) |
| Variant type | single nucleotide variant |
| Location | chr15:72731596-72731596 (GRCh38) |
| ClinVar | [VCV166734](https://www.ncbi.nlm.nih.gov/clinvar/variation/166734/) |

**All HGVS expressions:** `NC_000015.10:g.72731596T>C`, `NC_000015.9:g.73023937T>C`, `NG_009416.2:g.50412=`, `NM_001252678.2:c.390T>C`, `NM_001320665.2:c.837T>C`, `NM_033028.5:c.906T>C`, `NR_045565.2:n.985T>C`, `NR_045566.2:n.1240T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele.

- **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 -5.804, GERP -3.39 — fast-evolving / accelerated position
- CADD: **PHRED 3.329**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **100%** (eas) · FAF95 99.8% · FAF99 99.8% · 44,874/44,874 in the highest group · 1,602,754/1,614,126 alleles overall — common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 100% | 1 |
| Ashkenazi Jewish (not grpmax-eligible) | 100% | 1 |
| Amish (not grpmax-eligible) | 100% | 1 |
| Finnish (not grpmax-eligible) | 100% | 1 |
| European (non-Finnish) | 100% | 1 |
| South Asian | 100% | 1 |
| Middle Eastern | 99.4% | 1 |
| Admixed American | 99.3% | 1 |
| Remaining individuals (not grpmax-eligible) | 99.1% | 1 |
| African / African-American | 86.5% | 1 |

*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}

**BBS4** population constraint: LOEUF 0.953, pLI 6.813e-12, missense-Z -0.37523. *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):

- **BBS4-related ciliopathy** — Definitive (AR)

## Protein context {#protein}

Residue **302** lies in the 'interaction with pcm1' region.

AlphaFold model confidence (whole protein): pLDDT 78.36, 59% of residues very-high.

**1 experimental structure(s)** (PDB): [6XT9](https://www.rcsb.org/structure/6XT9).

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

*Describes the biological roles of BBS4 (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:** BBS4's established molecular role includes protein-macromolecule adaptor activity. p.Phe302= falls in the interaction with pcm1 region.


### Pathways affected {#pathways}

BBS4 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:** protein-macromolecule adaptor activity, dynactin binding, alpha-tubulin binding, beta-tubulin binding, RNA polymerase II-specific DNA-binding transcription factor binding.

**Biological process:** mitotic cytokinesis, centrosome cycle, regulation of cytokinesis, microtubule anchoring at centrosome, maintenance of protein location in nucleus, protein localization to cilium.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (9/9 Benign).

**Submission history:** 9 submissions (2014–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-03-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2014-03-03 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-14 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-02 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-28 |

## Associated conditions {#conditions}

[Bardet-Biedl syndrome](https://sugi.bio/atlas/disease/bardet-biedl-syndrome/), [Bardet-Biedl syndrome 4](https://sugi.bio/atlas/disease/bardet-biedl-syndrome-4/).

**Reported phenotype names (ClinVar):** Bardet-Biedl syndrome, not specified, Bardet-Biedl syndrome 4, not provided, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related BBS4 variant pages (same residue, condition, or type): [BBS4 c.1106+2T>A](/variant/bbs4-c-1106-plus-2t-a), [BBS4 c.1248+1G>A](/variant/bbs4-c-1248-plus-1g-a), [BBS4 c.1248+1G>T](/variant/bbs4-c-1248-plus-1g-t), [BBS4 c.1248+2T>C](/variant/bbs4-c-1248-plus-2t-c), [BBS4 c.1249-2A>C](/variant/bbs4-c-1249-minus-2a-c), [BBS4 c.157-2A>G](/variant/bbs4-c-157-minus-2a-g), [BBS4 c.157-3C>G](/variant/bbs4-c-157-minus-3c-g), [BBS4 c.220+1G>C](/variant/bbs4-c-220-plus-1g-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 166734). 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.*