# NM_016373.4(WWOX):c.909C>T (p.Phe303=)

https://sugi.bio/variant/wwox-p-phe303

## Summary

**WWOX p.Phe303= (c.909C>T)** is classified **Likely benign** in WWOX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). Very rare (popmax 0.000763%, nfe); Associated with developmental and epileptic encephalopathy, 1.

**At a glance:** Likely benign · review: Single submitter · rsID rs2083251216 · 1 submitter · 2 linked conditions · very rare (popmax 0.000763%, nfe)

## For patients & families {#patients}

This is a change in the WWOX gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to developmental and epileptic encephalopathy, 1.

*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) | Autosomal dominant, Autosomal recessive, X-linked dominant |
| Diagnostic panels | WWOX is a diagnostic-grade gene on 13 Genomics England panels |

**Commonly reported features of Infantile epileptic spasms syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Myoclonus — Very frequent (99-80%)
- Developmental regression — Very frequent (99-80%)
- Hypsarrhythmia — Very frequent (99-80%)
- Infantile spasms — Very frequent (99-80%)
- Abnormality of the nervous system — Frequent (79-30%)
- Abnormal skin morphology — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015298/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [WWOX](https://sugi.bio/atlas/gene/WWOX/) |
| Protein change (HGVS p.) | p.Phe303= |
| Coding change (HGVS c.) | c.909C>T |
| MANE Select transcript | [NM_016373](https://www.ncbi.nlm.nih.gov/nuccore/NM_016373) |
| dbSNP | [rs2083251216](https://www.ncbi.nlm.nih.gov/snp/rs2083251216/) |
| Variant type | single nucleotide variant |
| Location | chr16:78432605-78432605 (GRCh38) |
| ClinVar | [VCV2097938](https://www.ncbi.nlm.nih.gov/clinvar/variation/2097938/) |

**All HGVS expressions:** `NC_000016.10:g.78432605C>T`, `NC_000016.9:g.78466502C>T`, `NG_011698.1:g.337952C>T`, `NM_001291997.2:c.570C>T`, `NM_016373.4:c.909C>T`

## Computational & population evidence {#evidence}

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

- **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 5.969, GERP 2.29, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 10.09**. 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.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000763%** (nfe) · FAF95 0.000359% · FAF99 0.00026% · 9/1,180,046 in the highest group · 9/1,614,246 alleles overall — very rare (popmax 0.000763%, 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}

**WWOX** population constraint: LOEUF 1.82, pLI 3.1152e-33, missense-Z -5.6664; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, 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):

- **genetic developmental and epileptic encephalopathy** — Definitive (AR)

## Protein context {#protein}

Residue **303** lies in the 'interaction with mapt' region.

AlphaFold model confidence (whole protein): pLDDT 85.43, 56% of residues very-high.

**1 experimental structure(s)** (PDB): [1WMV](https://www.rcsb.org/structure/1WMV).

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

*Describes the biological roles of WWOX (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:** WWOX's established molecular role includes enzyme binding. p.Phe303= falls in the interaction with mapt region.


### Pathways affected {#pathways}

WWOX participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of the TFAP2 (AP-2) family of transcription factors](https://reactome.org/content/detail/R-HSA-8866907) | curated |
| [Negative regulation of activity of TFAP2 (AP-2) family transcription factors](https://reactome.org/content/detail/R-HSA-8866904) | curated |
| [Nuclear signaling by ERBB4](https://reactome.org/content/detail/R-HSA-1251985) | curated |

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

**Molecular function:** enzyme binding, identical protein binding.

**Biological process:** negative regulation of Wnt signaling pathway, cellular response to transforming growth factor beta stimulus.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-22.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-08-22 |

## Associated conditions {#conditions}

[developmental and epileptic encephalopathy, 1](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-1/), [autosomal recessive spinocerebellar ataxia 12](https://sugi.bio/atlas/disease/autosomal-recessive-spinocerebellar-ataxia-12/).

**Reported phenotype names (ClinVar):** Developmental and epileptic encephalopathy, 1, Autosomal recessive spinocerebellar ataxia 12, Tonic spasms with clustering, arrest of psychomotor development and hypsarrhythmia on EEG, X-Linked Infantile Spasm Syndrome, X-linked infantile spasms, West's syndrome, OHTAHARA SYNDROME, X-LINKED, INFANTILE SPASM SYNDROME, X-LINKED 1, Epileptic encephalopathy, early infantile, 1, SPINOCEREBELLAR ATAXIA WITH MENTAL RETARDATION AND EPILEPSY.

## Similar variants {#similar}

Related WWOX variant pages (same residue, condition, or type): [WWOX c.107+1G>A](/variant/wwox-c-107-plus-1g-a), [WWOX c.173-1G>C](/variant/wwox-c-173-minus-1g-c), [WWOX c.173-1G>T](/variant/wwox-c-173-minus-1g-t), [WWOX c.409+1G>C](/variant/wwox-c-409-plus-1g-c), [WWOX c.410-1G>A](/variant/wwox-c-410-minus-1g-a), [WWOX c.605+2T>C](/variant/wwox-c-605-plus-2t-c), [WWOX c.606-1G>A](/variant/wwox-c-606-minus-1g-a), [WWOX c.791+1G>T](/variant/wwox-c-791-plus-1g-t).

### 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 2097938). 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.*