# NM_016525.5(UBAP1):c.327_330dup (p.Ala111fs)

https://sugi.bio/variant/ubap1-p-ala111fs

## Summary

**UBAP1 p.Ala111fs (c.327_330dup)** is classified **Likely pathogenic** in UBAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). Associated with UBAP1-related disorder.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the UBAP1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to UBAP1-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 | [UBAP1](https://sugi.bio/atlas/gene/UBAP1/) |
| Protein change (HGVS p.) | p.Ala111fs |
| Coding change (HGVS c.) | c.327_330dup |
| MANE Select transcript | [NM_016525](https://www.ncbi.nlm.nih.gov/nuccore/NM_016525) |
| Variant type | Duplication |
| Location | chr9:34241351-34241352 (GRCh38) |
| ClinVar | [VCV4902990](https://www.ncbi.nlm.nih.gov/clinvar/variation/4902990/) |

**All HGVS expressions:** `NC_000009.11:g.34241350_34241353dup`, `NC_000009.12:g.34241352_34241355dup`, `NM_001171201.1:c.519_522dup`, `NM_001171202.1:c.435_438dup`, `NM_001171203.3:c.327_330dup`, `NM_001171204.3:c.327_330dup`, `NM_016525.5:c.327_330dup`, `NR_033243.3:n.648_651dup`

## 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 5.719, GERP 1.88, phastCons 0.998 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.285, pLI 0.99999), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 7**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**UBAP1** population constraint: LOEUF 0.285, pLI 0.99999, missense-Z 1.9839. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **111** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 63.60, 20% of residues very-high.

**3 experimental structure(s)** (PDB): [1WGN](https://www.rcsb.org/structure/1WGN), [4AE4](https://www.rcsb.org/structure/4AE4), [5LM1](https://www.rcsb.org/structure/5LM1).

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

*Describes the biological roles of UBAP1 (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:** UBAP1's established molecular role includes ubiquitin binding. p.Ala111fs falls in the disordered region. In Reactome, UBAP1 is annotated in disease pathway(s) including **Budding and maturation of HIV virion**, **HCMV Late Events**.

**Disease mechanism (Reactome):** UBAP1 loss or alteration is curated in [Budding and maturation of HIV virion](https://reactome.org/content/detail/R-HSA-162588), [HCMV Late Events](https://reactome.org/content/detail/R-HSA-9610379), [Membrane binding and targetting of GAG proteins](https://reactome.org/content/detail/R-HSA-174490).

### Pathways affected {#pathways}

UBAP1 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Budding and maturation of HIV virion](https://reactome.org/content/detail/R-HSA-162588) | curated |
| ⚕ [HCMV Late Events](https://reactome.org/content/detail/R-HSA-9610379) | curated |
| ⚕ [Membrane binding and targetting of GAG proteins](https://reactome.org/content/detail/R-HSA-174490) | curated |
| [Endosomal Sorting Complex Required For Transport (ESCRT)](https://reactome.org/content/detail/R-HSA-917729) | curated |
| [Late endosomal microautophagy](https://reactome.org/content/detail/R-HSA-9615710) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** ubiquitin binding.

**Biological process:** ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-09-01.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-09-01 |

## Associated conditions {#conditions}

[UBAP1-related disorder](https://sugi.bio/atlas/disease/ubap1-related-disorder/).

**Reported phenotype names (ClinVar):** UBAP1-related disorder, UBAP1-related condition.

## Similar variants {#similar}

Related UBAP1 variant pages (same residue, condition, or type): [UBAP1 p.Leu169Met](/variant/ubap1-p-leu169met), [UBAP1 p.Glu397Lys](/variant/ubap1-p-glu397lys), [UBAP1 p.Val144fs](/variant/ubap1-p-val144fs), [UBAP1 c.1083+4dup](/variant/ubap1-c-1083-plus-4dup), [UBAP1 c.-8+10dup](/variant/ubap1-c-minus-8-plus-10dup), [UBAP1 p.Asp99fs](/variant/ubap1-p-asp99fs), [UBAP1 p.Cys161fs](/variant/ubap1-p-cys161fs), [UBAP1 p.Glu97fs](/variant/ubap1-p-glu97fs).

### 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 4902990). 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.*