# NM_001039591.3(USP9X):c.4988T>A (p.Val1663Glu)

https://sugi.bio/variant/usp9x-p-val1663glu

## Summary

**USP9X p.Val1663Glu (c.4988T>A)** is classified **Uncertain significance** in USP9X (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-17). AlphaMissense: likely pathogenic (0.9849); Very rare (popmax 0.000112%, nfe); Associated with intellectual disability, X-linked 99, syndromic, female-restricted.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.000112%, nfe)

## For patients & families {#patients}

This is a change in the USP9X gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to intellectual disability, X-linked 99, syndromic, female-restricted.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024732/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [USP9X](https://sugi.bio/atlas/gene/USP9X/) |
| Protein change (HGVS p.) | p.Val1663Glu |
| Coding change (HGVS c.) | c.4988T>A |
| MANE Select transcript | [NM_001039591](https://www.ncbi.nlm.nih.gov/nuccore/NM_001039591) |
| Variant type | single nucleotide variant |
| Location | chrX:41205466-41205466 (GRCh38) |
| ClinVar | [VCV4882398](https://www.ncbi.nlm.nih.gov/clinvar/variation/4882398/) |

**All HGVS expressions:** `NC_000023.10:g.41064719T>A`, `NC_000023.11:g.41205466T>A`, `NG_012547.1:g.124832T>A`, `NM_001039590.3:c.4988T>A`, `NM_001039591.3:c.4988T>A`, `NM_001410748.1:c.5003T>A`, `NM_001410749.1:c.5003T>A`, `NM_001437534.1:c.5003T>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9849)
- REVEL 0.562 (indeterminate)
- SaProt LLR -4.249 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate
- Conservation: phyloP 6.194, GERP 2.15, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 24.5**. 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 0.35** across the covering region of the MANE Select transcript (41,198,659–41,216,430), spanning 17,771 bp — the region is depleted of missense variation. Chi-square p 2.5e-33. 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). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. 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. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. 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, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for USP9X (2,592 scored positions, the nearest 23 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *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 **0.000112%** (nfe) · 1/894,368 in the highest group · 1/1,208,298 alleles overall — very rare (popmax 0.000112%, 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}

**USP9X** population constraint: 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):

- **X-linked syndromic intellectual disability** — Definitive (XL)

## Protein context {#protein}

Residue **1663** lies in the usp domain; a UniProt-annotated variant site (in mrxs99f); a UniProt-annotated variant site (in mrxs99f; decreased expression levels).

AlphaFold model confidence (whole protein): pLDDT 80.06, 33% of residues very-high.

**4 experimental structure(s)** (PDB): [5VBD](https://www.rcsb.org/structure/5VBD), [5WCH](https://www.rcsb.org/structure/5WCH), [7YXX](https://www.rcsb.org/structure/7YXX), [7YXY](https://www.rcsb.org/structure/7YXY).

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

*Describes the biological roles of USP9X (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:** USP9X's established molecular role includes cysteine-type deubiquitinase activity. p.Val1663Glu falls in the usp domain.


### Pathways affected {#pathways}

USP9X participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Amyloid fiber formation](https://reactome.org/content/detail/R-HSA-977225) | curated |
| [Downregulation of SMAD2/3:SMAD4 transcriptional activity](https://reactome.org/content/detail/R-HSA-2173795) | curated |
| [RHOU GTPase cycle](https://reactome.org/content/detail/R-HSA-9013420) | curated |
| [RHOV GTPase cycle](https://reactome.org/content/detail/R-HSA-9013424) | curated |
| [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 |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | electronic |

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

**Molecular function:** cysteine-type deubiquitinase activity, K63-linked deubiquitinase activity, co-SMAD binding, deubiquitinase activity, molecular sequestering activity, K11-linked deubiquitinase activity.

**Biological process:** neuron migration, DNA alkylation repair, transforming growth factor beta receptor signaling pathway, protein import into peroxisome matrix, receptor recycling, protein deubiquitination, BMP signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-17.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Dasa | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-17 |

## Associated conditions {#conditions}

[intellectual disability, X-linked 99, syndromic, female-restricted](https://sugi.bio/atlas/disease/intellectual-disability-x-linked-99-syndromic-female-restricted/).

**Reported phenotype names (ClinVar):** Intellectual disability, X-linked 99, syndromic, female-restricted, INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 99, SYNDROMIC, FEMALE-RESTRICTED.

## Similar variants {#similar}

Related USP9X variant pages (same residue, condition, or type): [USP9X c.323-1G>A](/variant/usp9x-c-323-minus-1g-a), [USP9X p.Arg2366Ter](/variant/usp9x-p-arg2366ter), [USP9X p.Arg592Ter](/variant/usp9x-p-arg592ter), [USP9X p.Arg916Ter](/variant/usp9x-p-arg916ter), [USP9X p.Ala1948Thr](/variant/usp9x-p-ala1948thr), [USP9X p.Ala56Gly](/variant/usp9x-p-ala56gly), [USP9X p.His990Arg](/variant/usp9x-p-his990arg), [USP9X p.Ile1299Leu](/variant/usp9x-p-ile1299leu).

### 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 4882398). 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.*