# NM_033028.5(BBS4):c.464A>C (p.Gln155Pro)

https://sugi.bio/variant/bbs4-p-gln155pro

## Summary

**BBS4 p.Gln155Pro (c.464A>C)** is classified **Uncertain significance** in BBS4 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-09-19). AlphaMissense: likely pathogenic (0.7708); Very rare (popmax 0.000932%, nfe); Associated with BBS4-related disorder.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2065632499 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.000932%, nfe)

## For patients & families {#patients}

This is a change in the BBS4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to BBS4-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 | [BBS4](https://sugi.bio/atlas/gene/BBS4/) |
| Protein change (HGVS p.) | p.Gln155Pro |
| Coding change (HGVS c.) | c.464A>C |
| MANE Select transcript | [NM_033028](https://www.ncbi.nlm.nih.gov/nuccore/NM_033028) |
| dbSNP | [rs2065632499](https://www.ncbi.nlm.nih.gov/snp/rs2065632499/) |
| Variant type | single nucleotide variant |
| Location | chr15:72724532-72724532 (GRCh38) |
| ClinVar | [VCV2636498](https://www.ncbi.nlm.nih.gov/clinvar/variation/2636498/) |

**All HGVS expressions:** `NC_000015.10:g.72724532A>C`, `NC_000015.9:g.73016873A>C`, `NG_009416.2:g.43348A>C`, `NG_009416.3:g.43327A>C`, `NM_001252678.2:c.-53A>C`, `NM_001320665.2:c.464A>C`, `NM_033028.5:c.464A>C`, `NR_045565.2:n.543A>C`, `NR_045566.2:n.798A>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7708)
- REVEL 0.161 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -11.763 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- Conservation: phyloP 7.023, GERP 1.7, phastCons 0.998 — highly conserved (agrees)
- CADD: **PHRED 23.6**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.22 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 **0.000932%** (nfe) · FAF95 0.0005% · FAF99 0.000366% · 11/1,179,918 in the highest group · 11/1,613,904 alleles overall — very rare (popmax 0.000932%, nfe).

*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 **155** 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.Gln155Pro 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-19.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-09-19 |
| Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Uncertain significance | no assertion criteria provided | clinical testing | 2023-01-01 |

## Associated conditions {#conditions}

[BBS4-related disorder](https://sugi.bio/atlas/disease/bbs4-related-disorder/), [inherited retinal dystrophy](https://sugi.bio/atlas/disease/inherited-retinal-dystrophy/).

**Reported phenotype names (ClinVar):** BBS4-related disorder, Retinal dystrophy, BBS4-related condition, Inherited retinal dystrophy.

## Same-residue context {#hotspot}

Residue **155** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BBS4 p.Gln155Ter](/variant/bbs4-p-gln155ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BBS4 variant pages (same residue, condition, or type): [BBS4 p.Gln155Ter](/variant/bbs4-p-gln155ter), [BBS4 p.Gln155Lys](/variant/bbs4-p-gln155lys), [BBS4 p.Gln155=](/variant/bbs4-p-gln155), [BBS4 c.1248+2T>C](/variant/bbs4-c-1248-plus-2t-c), [BBS4 c.157-3C>G](/variant/bbs4-c-157-minus-3c-g), [BBS4 c.220+1G>C](/variant/bbs4-c-220-plus-1g-c), [BBS4 c.24+1G>A](/variant/bbs4-c-24-plus-1g-a), [BBS4 c.332+8T>C](/variant/bbs4-c-332-plus-8t-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 2636498). 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.*