# NM_001040142.2(SCN2A):c.4989del (p.Ile1663fs)

https://sugi.bio/variant/scn2a-p-ile1663fs

## Summary

**SCN2A p.Ile1663fs (c.4989del)** is classified **Likely pathogenic** in SCN2A (ClinVar, Single submitter, 1 submitter). No gnomAD frequency available for this variant; Associated with developmental and epileptic encephalopathy, 11.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1702009872 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the SCN2A gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to developmental and epileptic encephalopathy, 11.

*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/0015699/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SCN2A](https://sugi.bio/atlas/gene/SCN2A/) |
| Protein change (HGVS p.) | p.Ile1663fs |
| Coding change (HGVS c.) | c.4989del |
| MANE Select transcript | [NM_001040142](https://www.ncbi.nlm.nih.gov/nuccore/NM_001040142) |
| dbSNP | [rs1702009872](https://www.ncbi.nlm.nih.gov/snp/rs1702009872/) |
| Variant type | Deletion |
| Location | chr2:165388795-165388795 (GRCh38) |
| ClinVar | [VCV983149](https://www.ncbi.nlm.nih.gov/clinvar/variation/983149/) |

**All HGVS expressions:** `NC_000002.11:g.166245305del`, `NC_000002.12:g.165388795del`, `NG_008143.1:g.154394del`, `NM_001040142.2:c.4989del`, `NM_001040143.2:c.4989del`, `NM_001040143.2:c.4989delC`, `NM_001371246.1:c.4989del`, `NM_001371247.1:c.4989del`, `NM_021007.3:c.4989del`

## 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 7.711, GERP 1.92, 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 0.161, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (27 of 27)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**SCN2A** population constraint: LOEUF 0.161, pLI 1, missense-Z 8.7269; 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):

- **complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}

Residue **1663** lies in a UniProt-annotated variant site (found in a patient with intractable epilepsy and severe mental decline; likely pathogenic; non-conducting; loss of voltage-gated sodium channel activity; dominant-negative); a UniProt-annotated variant site (found in a patient with schizofrenia; uncertain significance); a UniProt-annotated variant site (found in a patient with autism spectrum disorder; likely pathogenic); a UniProt-annotated variant site (found in a patient with autism spectrum disorder; likely pathogenic; loss of voltage-gated sodium channel activity; non-conducting); a UniProt-annotated variant site (in dee11); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 69.28, 17% of residues very-high.

**5 experimental structure(s)** (PDB): [2KAV](https://www.rcsb.org/structure/2KAV), [4JPZ](https://www.rcsb.org/structure/4JPZ), [4RLY](https://www.rcsb.org/structure/4RLY), [6BUT](https://www.rcsb.org/structure/6BUT), [6J8E](https://www.rcsb.org/structure/6J8E).

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

*Describes the biological roles of SCN2A (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:** SCN2A's established molecular role includes voltage-gated sodium channel activity.


### Pathways affected {#pathways}

SCN2A participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Phase 0 - rapid depolarisation](https://reactome.org/content/detail/R-HSA-5576892) | curated |
| [Interaction between L1 and Ankyrins](https://reactome.org/content/detail/R-HSA-445095) | electronic |
| [Sensory perception of sweet, bitter, and umami (glutamate) taste](https://reactome.org/content/detail/R-HSA-9717207) | electronic |

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

**Molecular function:** voltage-gated sodium channel activity, calmodulin binding.

**Biological process:** neuronal action potential.

## Clinical significance {#significance}

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

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia | Likely pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[developmental and epileptic encephalopathy, 11](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-11/).

**Reported phenotype names (ClinVar):** Developmental and epileptic encephalopathy, 11, Early infantile epileptic encephalopathy 11.

## Similar variants {#similar}

Related SCN2A variant pages (same residue, condition, or type): [SCN2A p.Ile1663=](/variant/scn2a-p-ile1663), [SCN2A p.Leu577fs](/variant/scn2a-p-leu577fs), [SCN2A p.Phe1661fs](/variant/scn2a-p-phe1661fs), [SCN2A p.Ser484fs](/variant/scn2a-p-ser484fs), [SCN2A c.605+4_605+7del](/variant/scn2a-c-605-plus-4-605-plus-7del), [SCN2A p.Glu1956_Asn1957del](/variant/scn2a-p-glu1956-asn1957del), [SCN2A p.Lys1946del](/variant/scn2a-p-lys1946del), [SCN2A c.1034+1del](/variant/scn2a-c-1034-plus-1del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 983149). 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.*