# NM_001098536.2(USP5):c.1558C>T (p.Pro520Ser)

https://sugi.bio/variant/usp5-p-pro520ser

## Summary

**USP5 p.Pro520Ser (c.1558C>T)** is classified **Uncertain significance** in USP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-20). AlphaMissense: ambiguous (0.4171); Ultra-rare (popmax 0.0147%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · ultra-rare (popmax 0.0147%, afr)

## For patients & families {#patients}

This is a change in the USP5 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [USP5](https://sugi.bio/atlas/gene/USP5/) |
| Protein change (HGVS p.) | p.Pro520Ser |
| Coding change (HGVS c.) | c.1558C>T |
| MANE Select transcript | [NM_001098536](https://www.ncbi.nlm.nih.gov/nuccore/NM_001098536) |
| Variant type | single nucleotide variant |
| Location | chr12:6861502-6861502 (GRCh38) |
| ClinVar | [VCV3467218](https://www.ncbi.nlm.nih.gov/clinvar/variation/3467218/) |

**All HGVS expressions:** `NC_000012.11:g.6970666C>T`, `NC_000012.12:g.6861502C>T`, `NM_001098536.2:c.1558C>T`, `NM_001382588.1:c.1432C>T`, `NM_001382589.1:c.1432C>T`, `NM_001382590.1:c.1420C>T`, `NM_001382591.1:c.1486C>T`, `NM_003481.3:c.1558C>T`, `NR_168449.1:n.1588C>T`, `NR_168450.1:n.1403C>T`, `NR_168451.1:n.1518C>T`, `NR_168452.1:n.1588C>T`, `NR_168455.1:n.1588C>T`, `NR_168456.1:n.1588C>T`, `NR_168457.1:n.1500C>T`, `NR_168458.1:n.1714C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.4171) — no call either way
- REVEL 0.086 (moderately benign-leaning)
- SaProt LLR -14.733 (damaging)
- → **In-silico consensus:** SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate
- Conservation: phyloP 7.715, GERP 2.54, phastCons 1 — highly conserved
- CADD: **PHRED 25.3**. 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 0.65** across the covering region of the MANE Select transcript (6,852,180–6,863,319), spanning 11,139 bp. Chi-square p 4e-24. 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 (C>A, Δ0.27 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 **0.0147%** (afr) · FAF95 0.00818% · FAF99 0.00635% · 11/74,706 in the highest group · 11/1,600,436 alleles overall — ultra-rare (popmax 0.0147%, afr).

*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}

**USP5** population constraint: LOEUF 0.329, pLI 1, missense-Z 4.3427. *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 **520** lies in the usp domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 81.40, 50% of residues very-high.

**12 experimental structure(s)** (PDB): [2DAG](https://www.rcsb.org/structure/2DAG), [2DAK](https://www.rcsb.org/structure/2DAK), [2G43](https://www.rcsb.org/structure/2G43), [2G45](https://www.rcsb.org/structure/2G45), [3IHP](https://www.rcsb.org/structure/3IHP), [6DXH](https://www.rcsb.org/structure/6DXH).

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

*Describes the biological roles of USP5 (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:** USP5's established molecular role includes cysteine-type deubiquitinase activity. p.Pro520Ser falls in the usp domain.


### Pathways affected {#pathways}

USP5 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of active ubiquitin: roles of E1 and E2 enzymes](https://reactome.org/content/detail/R-HSA-8866652) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |

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

**Molecular function:** cysteine-type deubiquitinase activity, ubiquitin binding, deubiquitinase activity.

**Biological process:** negative regulation of T cell mediated immune response to tumor cell, negative regulation of proteasomal ubiquitin-dependent protein catabolic process, positive regulation of proteasomal ubiquitin-dependent protein catabolic process, protein K48-linked deubiquitination, negative regulation of ubiquitin-dependent protein catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-09-20.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-20 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related USP5 variant pages (same residue, condition, or type): [USP5 p.Leu380=](/variant/usp5-p-leu380), [USP5 p.Leu489=](/variant/usp5-p-leu489), [USP5 p.Pro609=](/variant/usp5-p-pro609), [USP5 p.Val18=](/variant/usp5-p-val18), [USP5 p.Ala495Thr](/variant/usp5-p-ala495thr), [USP5 p.Ala549Val](/variant/usp5-p-ala549val), [USP5 p.Ala718Thr](/variant/usp5-p-ala718thr), [USP5 p.Ala780Ser](/variant/usp5-p-ala780ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3467218). 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.*