# NM_003470.3(USP7):c.1226T>C (p.Phe409Ser)

https://sugi.bio/variant/usp7-p-phe409ser

## Summary

**USP7 p.Phe409Ser (c.1226T>C)** is classified **Uncertain significance** in USP7 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-20). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with Hao-Fountain syndrome due to USP7 mutation.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the USP7 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Phe409Ser |
| Coding change (HGVS c.) | c.1226T>C |
| MANE Select transcript | [NM_003470](https://www.ncbi.nlm.nih.gov/nuccore/NM_003470) |
| Variant type | single nucleotide variant |
| Location | chr16:8908386-8908386 (GRCh38) |
| ClinVar | [VCV4879516](https://www.ncbi.nlm.nih.gov/clinvar/variation/4879516/) |

**All HGVS expressions:** `NC_000016.10:g.8908386A>G`, `NC_000016.9:g.9002243A>G`, `NG_046847.1:g.60099T>C`, `NM_001286457.2:c.1178T>C`, `NM_001286458.2:c.929T>C`, `NM_001321858.2:c.1052T>C`, `NM_003470.3:c.1226T>C`, `NR_135826.2:n.1248T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9999)
- REVEL 0.733 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.689 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.133, GERP 2.43, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 6%** most-pathogenic-predicted substitutions in USP7 (of 6,531 modeled).
- CADD: **PHRED 26.9**. 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 0.23** across the covering region of the MANE Select transcript (8,905,296–8,910,775), spanning 5,479 bp — the region is depleted of missense variation. Chi-square p 2.3e-19. 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, A>C, IS in the release and scores Δ0.54 donor gain, 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **409** 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); a β-strand.

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.Phe409Ser 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-04-20.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Clinical Genomics Laboratory, Washington University in St. Louis | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-04-20 |

## 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.

## Same-residue context {#hotspot}

Residue **409** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [USP7 p.Phe409fs](/variant/usp7-p-phe409fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## 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.Glu60Ter](/variant/usp7-p-glu60ter).

### 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 4879516). 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.*