# NM_005154.5(USP8):c.2152T>C (p.Ser718Pro)

https://sugi.bio/variant/usp8-p-ser718pro

## Summary

**USP8 p.Ser718Pro (c.2152T>C)** is classified **Pathogenic** in USP8 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2017-09-26). AlphaMissense: likely pathogenic (0.994); Very rare (popmax 8.47e-05%, nfe); Associated with Cushing disease due to pituitary adenoma.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs672601307 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the USP8 gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to Cushing disease due to pituitary adenoma.

*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) | Not applicable |
| Age of onset (of this condition) | Adult |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 42 registered for this condition — see ClinicalTrials.gov |

**Commonly reported features of Cushing disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Increased circulating cortisol level — Very frequent (99-80%)
- Paradoxical increased cortisol secretion on dexamethasone suppression test — Very frequent (99-80%)
- Pituitary corticotropic cell adenoma — Very frequent (99-80%)
- Increased urinary cortisol level — Very frequent (99-80%)
- Osteoporosis — Frequent (79-30%)
- Hyperpigmentation of the skin — Frequent (79-30%)
- Thin skin — Frequent (79-30%)
- Bruising susceptibility — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012867/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [USP8](https://sugi.bio/atlas/gene/USP8/) |
| Protein change (HGVS p.) | p.Ser718Pro |
| Coding change (HGVS c.) | c.2152T>C |
| MANE Select transcript | [NM_005154](https://www.ncbi.nlm.nih.gov/nuccore/NM_005154) |
| dbSNP | [rs672601307](https://www.ncbi.nlm.nih.gov/snp/rs672601307/) |
| Variant type | single nucleotide variant |
| Location | chr15:50490443-50490443 (GRCh38) |
| ClinVar | [VCV161992](https://www.ncbi.nlm.nih.gov/clinvar/variation/161992/) |

**All HGVS expressions:** `NC_000015.10:g.50490443T>C`, `NC_000015.9:g.50782640T>C`, `NG_047101.1:g.71067T>C`, `NM_001128610.3:c.2152T>C`, `NM_001283049.2:c.1834T>C`, `NM_005154.5:c.2152T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.994) — concordant with the pathogenic call
- REVEL 0.247 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -10.706 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- Conservation: phyloP 7.87, GERP 2.18, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 6%** most-pathogenic-predicted substitutions in USP8 (of 6,588 modeled).
- CADD: **PHRED 25.5**. 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 0.93** across the covering region of the MANE Select transcript (50,476,937–50,492,715), spanning 15,778 bp. Chi-square p 0.12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, T>A, IS in the release and scores Δ0.27 acceptor loss, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,014 in the highest group · 1/1,614,074 alleles overall — very rare (popmax 8.47e-05%, 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}

**USP8** population constraint: LOEUF 0.28, pLI 1, missense-Z 2.9342. *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 **718** lies in a modified residue (phosphoserine); a UniProt-annotated variant site (in pita4; uncertain significance; somatic mutation); a UniProt-annotated variant site (in pita4; uncertain significance; somatic mutation; localizes to nucleus instead of cytoplasm); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 71.98, 37% of residues very-high.

**9 experimental structure(s)** (PDB): [1WHB](https://www.rcsb.org/structure/1WHB), [2A9U](https://www.rcsb.org/structure/2A9U), [2GFO](https://www.rcsb.org/structure/2GFO), [2GWF](https://www.rcsb.org/structure/2GWF), [3N3K](https://www.rcsb.org/structure/3N3K), [6F09](https://www.rcsb.org/structure/6F09).

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

*Describes the biological roles of USP8 (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:** USP8's established molecular role includes cysteine-type deubiquitinase activity. p.Ser718Pro falls in the disordered region.


### Pathways affected {#pathways}

USP8 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Downregulation of ERBB2:ERBB3 signaling](https://reactome.org/content/detail/R-HSA-1358803) | curated |
| [Negative regulation of MET activity](https://reactome.org/content/detail/R-HSA-6807004) | curated |
| [Regulation of FZD by ubiquitination](https://reactome.org/content/detail/R-HSA-4641263) | 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, cadherin binding, K63-linked deubiquitinase activity, K48-linked deubiquitinase activity.

**Biological process:** mitotic cytokinesis, protein deubiquitination, regulation of protein stability, regulation of protein localization, protein K63-linked deubiquitination, protein K48-linked deubiquitination.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2017-09-26.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2014–2017); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2017-09-26 |
| Institute of Human Genetics Munich, TUM University Hospital | Pathogenic | no assertion criteria provided | research | 2014-11-18 |

## Associated conditions {#conditions}

[Cushing disease due to pituitary adenoma](https://sugi.bio/atlas/disease/cushing-disease-due-to-pituitary-adenoma/).

**Reported phenotype names (ClinVar):** Pituitary dependent hypercortisolism, Cushing disease due to pituitary adenoma, Pituitary ACTH Hypersecretion, Pituitary adenoma, acth-secreting, somatic, CUSHING DISEASE, PITUITARY, PITUITARY ADENOMA 4, ACTH-SECRETING.

## Same-residue context {#hotspot}

Residue **718** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [USP8 p.Ser718Cys](/variant/usp8-p-ser718cys). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related USP8 variant pages (same residue, condition, or type): [USP8 p.Ser718Cys](/variant/usp8-p-ser718cys), [USP8 p.Pro703His](/variant/usp8-p-pro703his), [USP8 p.Pro720Arg](/variant/usp8-p-pro720arg), [USP8 p.Ser719del](/variant/usp8-p-ser719del), [USP8 p.Arg133Trp](/variant/usp8-p-arg133trp), [USP8 p.Phe875Ser](/variant/usp8-p-phe875ser), [USP8 c.104+16C>T](/variant/usp8-c-104-plus-16c-t), [USP8 c.250-8A>C](/variant/usp8-c-250-minus-8a-c).

### 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 161992). 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.*