# NM_001040142.2(SCN2A):c.4988T>C (p.Ile1663Thr)

https://sugi.bio/variant/scn2a-p-ile1663thr

## Summary

**SCN2A p.Ile1663Thr (c.4988T>C)** is classified **Uncertain significance** in SCN2A (ClinVar, Single submitter, 2 submitters; last evaluated 2022-12-19). AlphaMissense: likely pathogenic (0.9243); Absent from gnomAD v4.1; Associated with Dravet syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2105402379 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the SCN2A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Dravet syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 91 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010430/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.Ile1663Thr |
| Coding change (HGVS c.) | c.4988T>C |
| MANE Select transcript | [NM_001040142](https://www.ncbi.nlm.nih.gov/nuccore/NM_001040142) |
| dbSNP | [rs2105402379](https://www.ncbi.nlm.nih.gov/snp/rs2105402379/) |
| Variant type | single nucleotide variant |
| Location | chr2:165388794-165388794 (GRCh38) |
| ClinVar | [VCV1342668](https://www.ncbi.nlm.nih.gov/clinvar/variation/1342668/) |

**All HGVS expressions:** `NC_000002.11:g.166245304T>C`, `NC_000002.12:g.165388794T>C`, `NG_008143.1:g.154393T>C`, `NM_001040142.2:c.4988T>C`, `NM_001040143.2:c.4988T>C`, `NM_001371246.1:c.4988T>C`, `NM_001371247.1:c.4988T>C`, `NM_021007.2:c.4988T>C`, `NM_021007.3:c.4988T>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** (0.9243)
- REVEL 0.967 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.429 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.711, GERP 1.92, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 23.1**. 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 0.06** across the covering region of the MANE Select transcript (165,388,664–165,388,812), spanning 148 bp — the region is depleted of missense variation. Chi-square p 2.7e-14. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **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}

**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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-12-19.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Neurology Department, Shenzhen Children's Hospital | Likely pathogenic | no assertion criteria provided | clinical testing | 2022-02-16 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-12-19 |

## Associated conditions {#conditions}

[Dravet syndrome](https://sugi.bio/atlas/disease/dravet-syndrome/).

**Reported phenotype names (ClinVar):** Severe myoclonic epilepsy in infancy, not provided, none provided, Dravet syndrome, Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), Severe Myoclonic Epilepsy in Infancy (SMEI), SEVERE MYOCLONIC EPILEPSY OF INFANCY, DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 6A.

## Same-residue context {#hotspot}

Residue **1663** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [SCN2A p.Ile1663fs](/variant/scn2a-p-ile1663fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related SCN2A variant pages (same residue, condition, or type): [SCN2A p.Ile1663=](/variant/scn2a-p-ile1663), [SCN2A p.Ile1663Leu](/variant/scn2a-p-ile1663leu), [SCN2A p.Ile1663fs](/variant/scn2a-p-ile1663fs), [SCN2A p.Ala1773Thr](/variant/scn2a-p-ala1773thr), [SCN2A p.Arg220Gly](/variant/scn2a-p-arg220gly), [SCN2A p.Arg853Gln](/variant/scn2a-p-arg853gln), [SCN2A p.Gly899Asp](/variant/scn2a-p-gly899asp), [SCN2A p.Leu1611Pro](/variant/scn2a-p-leu1611pro).

### 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 1342668). 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.*