# NM_001040142.2(SCN2A):c.4989C>T (p.Ile1663=)

https://sugi.bio/variant/scn2a-p-ile1663

## Summary

**SCN2A p.Ile1663= (c.4989C>T)** is classified **Benign/Likely benign** in SCN2A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-19). Rare (popmax 0.153%, amr); Associated with Inborn genetic diseases.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs373347369 · 5 submitters · 3 linked conditions · rare (popmax 0.153%, amr)

## For patients & families {#patients}

This is a change in the SCN2A gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to Inborn genetic diseases.

*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:** [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.Ile1663= |
| Coding change (HGVS c.) | c.4989C>T |
| MANE Select transcript | [NM_001040142](https://www.ncbi.nlm.nih.gov/nuccore/NM_001040142) |
| dbSNP | [rs373347369](https://www.ncbi.nlm.nih.gov/snp/rs373347369/) |
| Variant type | single nucleotide variant |
| Location | chr2:165388795-165388795 (GRCh38) |
| ClinVar | [VCV331736](https://www.ncbi.nlm.nih.gov/clinvar/variation/331736/) |

**All HGVS expressions:** `NC_000002.11:g.166245305C>T`, `NC_000002.12:g.165388795C>T`, `NG_008143.1:g.154394C>T`, `NM_001040142.2:c.4989C>T`, `NM_001040143.2:c.4989C>T`, `NM_001371246.1:c.4989C>T`, `NM_001371247.1:c.4989C>T`, `NM_021007.3:c.4989C>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 -10.969, GERP -3.53 — fast-evolving / accelerated position
- CADD: **PHRED 2.026**. 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 **0.153%** (amr) · FAF95 0.128% · FAF99 0.119% · 92/59,998 in the highest group · 104/1,614,102 alleles overall — rare (popmax 0.153%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.153% | 652 |
| East Asian | 0.00669% | 14,955 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,253 |
| African / African-American | 0.00267% | 37,521 |
| South Asian | 0.0011% | 91,088 |
| European (non-Finnish) | 0.000339% | 294,997 |

*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, triplosensitivity 0 (0–3 scale). *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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-19.

**Submitter consensus:** conflicting (4 Benign, 1 Likely benign).

**Submission history:** 5 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-09-10 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Genetic Services Laboratory, University of Chicago | Benign | criteria provided, single submitter | clinical testing | 2017-09-07 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2016-08-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-19 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [seizures, benign familial infantile, 3](https://sugi.bio/atlas/disease/seizures-benign-familial-infantile-3/), [developmental and epileptic encephalopathy, 11](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-11/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Seizures, benign familial infantile, 3, not specified, Developmental and epileptic encephalopathy, 11, AllHighlyPenetrant, Early infantile epileptic encephalopathy 11, CONVULSIONS, BENIGN FAMILIAL INFANTILE, 3, Familial neonatal seizures.

## 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.Ile1663fs](/variant/scn2a-p-ile1663fs), [SCN2A p.Ile1663Thr](/variant/scn2a-p-ile1663thr), [SCN2A p.Ile1663Leu](/variant/scn2a-p-ile1663leu), [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 2026-10-06); 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 331736). 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.*