# NM_033028.5(BBS4):c.1136C>T (p.Ala379Val)

https://sugi.bio/variant/bbs4-p-ala379val

## Summary

**BBS4 p.Ala379Val (c.1136C>T)** is classified **Benign/Likely benign** in BBS4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-14). AlphaMissense: likely pathogenic (0.6646); Very rare (popmax 0.00153%, nfe); Associated with Bardet-Biedl syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs147269475 · 3 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00153%, nfe)

## For patients & families {#patients}

This is a change in the BBS4 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 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.Ala379Val |
| Coding change (HGVS c.) | c.1136C>T |
| MANE Select transcript | [NM_033028](https://www.ncbi.nlm.nih.gov/nuccore/NM_033028) |
| dbSNP | [rs147269475](https://www.ncbi.nlm.nih.gov/snp/rs147269475/) |
| Variant type | single nucleotide variant |
| Location | chr15:72735854-72735854 (GRCh38) |
| ClinVar | [VCV1135622](https://www.ncbi.nlm.nih.gov/clinvar/variation/1135622/) |

**All HGVS expressions:** `NC_000015.10:g.72735854C>T`, `NC_000015.9:g.73028195C>T`, `NG_009416.2:g.54670C>T`, `NM_001252678.2:c.620C>T`, `NM_001320665.2:c.1067C>T`, `NM_033028.4:c.1136C>T`, `NM_033028.5:c.1136C>T`, `NR_045565.2:n.1215C>T`, `NR_045566.2:n.1470C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.6646)
- REVEL 0.636 (indeterminate)
- SaProt LLR -16.003 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- SpliceAI predicts **acceptor gain** (Δ 0.31) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 6.001, GERP 1.58, 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 1.09** across the covering region of the MANE Select transcript (72,686,228–72,737,584), spanning 51,356 bp. Chi-square p 0.035. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.03**, donor loss **0.00**, acceptor gain **0.31**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.31**, donor gain **0.00**.
- Pangolin: Δ**0.30** (gain), gain 0.30 / loss 0.12. Agrees with SpliceAI. 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 **0.00153%** (nfe) · FAF95 0.000953% · FAF99 0.000787% · 18/1,180,032 in the highest group · 199/1,614,046 alleles overall — very rare (popmax 0.00153%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.507% | 197 |
| Remaining individuals (not grpmax-eligible) | 0.0496% | 2,016 |
| European (non-Finnish) (grpmax) | 0.00153% | 65,557 |

Ashkenazi Jewish 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}

**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 **379** lies in the 'required for localization to centrosomes' 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.Ala379Val falls in the required for localization to centrosomes 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/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-14.

**Submitter consensus:** conflicting (2 Likely benign, 1 Benign).

**Submission history:** 3 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-10-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-14 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-06-10 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Bardet-Biedl syndrome, BBS4-related disorder, not specified, BBS4-related condition, AllHighlyPenetrant.

## Similar variants {#similar}

Related BBS4 variant pages (same residue, condition, or type): [BBS4 p.Ala379Ser](/variant/bbs4-p-ala379ser), [BBS4 p.Ala379Thr](/variant/bbs4-p-ala379thr), [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).

### 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 1135622). 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.*