# NM_152564.5(VPS13B):c.163_166del (p.Phe55fs)

https://sugi.bio/variant/vps13b-p-phe55fs

## Summary

**VPS13B p.Phe55fs (c.163_166del)** is classified **Pathogenic** in VPS13B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-26). No gnomAD frequency available for this variant; Associated with Cohen syndrome.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2488267195 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the VPS13B gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Cohen 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.*

|  |  |
| --- | --- |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006126/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [VPS13B](https://sugi.bio/atlas/gene/VPS13B/) |
| Protein change (HGVS p.) | p.Phe55fs |
| Coding change (HGVS c.) | c.163_166del |
| MANE Select transcript | [NM_152564](https://www.ncbi.nlm.nih.gov/nuccore/NM_152564) |
| dbSNP | [rs2488267195](https://www.ncbi.nlm.nih.gov/snp/rs2488267195/) |
| Variant type | Deletion |
| Location | chr8:99038436-99038439 (GRCh38) |
| ClinVar | [VCV2859326](https://www.ncbi.nlm.nih.gov/clinvar/variation/2859326/) |

**All HGVS expressions:** `LRG_351:g.30173_30176del`, `LRG_351t1:c.163_166del`, `LRG_351t2:c.163_166del`, `LRG_351t3:c.163_166del`, `LRG_351t4:c.163_166del`, `NC_000008.10:g.100050666_100050669del`, `NC_000008.11:g.99038438_99038441del`, `NG_007098.2:g.30173_30176del`, `NM_015243.3:c.163_166del`, `NM_017890.5:c.163_166del`, `NM_152564.5:c.163_166del`, `NM_181661.3:c.163_166del`, `NR_047582.2:n.266_269del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.535, GERP 2.59, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.708, pLI 2.3165e-55. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 62**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**VPS13B** population constraint: LOEUF 0.708, pLI 2.3165e-55, missense-Z 2.4646. *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):

- **Cohen syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **55** lies in the chorein n-terminal domain; a UniProt-annotated variant site (in coh1).

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-04-26.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-04-26 |

## Associated conditions {#conditions}

[Cohen syndrome](https://sugi.bio/atlas/disease/cohen-syndrome/).

**Reported phenotype names (ClinVar):** Cohen syndrome, Cutis verticis gyrata, retinitis pigmentosa, and sensorineural deafness, PEPPER SYNDROME.

## Similar variants {#similar}

Related VPS13B variant pages (same residue, condition, or type): [VPS13B p.Phe55=](/variant/vps13b-p-phe55), [VPS13B p.Ala2763fs](/variant/vps13b-p-ala2763fs), [VPS13B p.Ala3695fs](/variant/vps13b-p-ala3695fs), [VPS13B p.Arg1779fs](/variant/vps13b-p-arg1779fs), [VPS13B p.Arg2326_Ile2327insTer](/variant/vps13b-p-arg2326-ile2327inster), [VPS13B p.Arg3840fs](/variant/vps13b-p-arg3840fs), [VPS13B p.Asn2406fs](/variant/vps13b-p-asn2406fs), [VPS13B p.Asp306fs](/variant/vps13b-p-asp306fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2859326). 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.*