# NM_003470.3(USP7):c.786_787del (p.Arg262fs)

https://sugi.bio/variant/usp7-p-arg262fs

## Summary

**USP7 p.Arg262fs (c.786_787del)** is classified **Pathogenic** in USP7 (ClinVar, Single submitter, 1 submitter). Associated with Hao-Fountain syndrome due to USP7 mutation.

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

## For patients & families {#patients}

This is a change in the USP7 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Hao-Fountain syndrome due to USP7 mutation.

*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.*

|  |  |
| --- | --- |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | USP7 is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026917/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [USP7](https://sugi.bio/atlas/gene/USP7/) |
| Protein change (HGVS p.) | p.Arg262fs |
| Coding change (HGVS c.) | c.786_787del |
| MANE Select transcript | [NM_003470](https://www.ncbi.nlm.nih.gov/nuccore/NM_003470) |
| Variant type | Microsatellite |
| Location | chr16:8917090-8917091 (GRCh38) |
| ClinVar | [VCV4685497](https://www.ncbi.nlm.nih.gov/clinvar/variation/4685497/) |

**All HGVS expressions:** `NC_000016.10:g.8917090CT[1]`, `NC_000016.9:g.9010947CT[1]`, `NG_046847.1:g.51392AG[1]`, `NM_001286457.2:c.738_739del`, `NM_001286458.2:c.489_490del`, `NM_001321858.2:c.612_613del`, `NM_003470.3:c.786_787del`, `NR_135826.2:n.806AG[1]`

## 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 10.907, GERP 2.29, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.085, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 31**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite 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}

**USP7** population constraint: LOEUF 0.085, pLI 1, missense-Z 6.8707; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **Hao-Fountain syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **262** lies in the usp domain; a UniProt-annotated variant site (in hafous; when expressed in usp7-deficient cells does not rescue defective endosomal protein recycling and reduced f-actin levels); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 86.50, 64% of residues very-high.

**86 experimental structure(s)** (PDB): [12ZJ](https://www.rcsb.org/structure/12ZJ), [1NB8](https://www.rcsb.org/structure/1NB8), [1NBF](https://www.rcsb.org/structure/1NBF), [1YY6](https://www.rcsb.org/structure/1YY6), [1YZE](https://www.rcsb.org/structure/1YZE), [2F1W](https://www.rcsb.org/structure/2F1W) — incl. mutant structure 5KYB.

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

*Describes the biological roles of USP7 (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:** USP7's established molecular role includes p53 binding. p.Arg262fs falls in the usp domain.


### Pathways affected {#pathways}

USP7 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Dual incision in TC-NER](https://reactome.org/content/detail/R-HSA-6782135) | curated |
| [Formation of TC-NER Pre-Incision Complex](https://reactome.org/content/detail/R-HSA-6781823) | curated |
| [Gap-filling DNA repair synthesis and ligation in TC-NER](https://reactome.org/content/detail/R-HSA-6782210) | curated |
| [Regulation of PTEN localization](https://reactome.org/content/detail/R-HSA-8948747) | curated |
| [Regulation of TP53 Degradation](https://reactome.org/content/detail/R-HSA-6804757) | curated |
| [Synthesis of active ubiquitin: roles of E1 and E2 enzymes](https://reactome.org/content/detail/R-HSA-8866652) | curated |
| [Transcription-Coupled Nucleotide Excision Repair (TC-NER)](https://reactome.org/content/detail/R-HSA-6781827) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |

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

**Molecular function:** p53 binding, cysteine-type endopeptidase activity, cysteine-type deubiquitinase activity, deubiquitinase activity, K48-linked deubiquitinase activity.

**Biological process:** transcription-coupled nucleotide-excision repair, DNA alkylation repair, regulation of tumor necrosis factor-mediated signaling pathway, protein deubiquitination, regulation of protein stability, negative regulation of proteasomal ubiquitin-dependent protein catabolic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Imagene.me medical diagnostic laboratory, IMAGENE.ME SA | Pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[Hao-Fountain syndrome due to USP7 mutation](https://sugi.bio/atlas/disease/hao-fountain-syndrome-due-to-usp7-mutation/).

**Reported phenotype names (ClinVar):** Hao-Fountain syndrome due to USP7 mutation, USP7-Related Hao Fountain Syndrome.

## Similar variants {#similar}

Related USP7 variant pages (same residue, condition, or type): [USP7 p.Arg1018Ter](/variant/usp7-p-arg1018ter), [USP7 p.Arg508Ter](/variant/usp7-p-arg508ter), [USP7 p.Arg793Cys](/variant/usp7-p-arg793cys), [USP7 c.2919+1G>A](/variant/usp7-c-2919-plus-1g-a), [USP7 c.3040-1G>A](/variant/usp7-c-3040-minus-1g-a), [USP7 c.3111+1G>A](/variant/usp7-c-3111-plus-1g-a), [USP7 p.Arg1023Ter](/variant/usp7-p-arg1023ter), [USP7 p.Cys488fs](/variant/usp7-p-cys488fs).

### 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 4685497). 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.*