# NM_001330260.2(SCN8A):c.5943GAG[1] (p.Ter1981=)

https://sugi.bio/variant/scn8a-p-ter1981

## Summary

**SCN8A p.Ter1981= (c.5943GAG[1])** is classified **Benign/Likely benign** in SCN8A (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-03). Rare (popmax 0.693%, afr); Associated with early-infantile DEE.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs555793953 · 8 submitters · 1 linked condition · rare (popmax 0.693%, afr)

## For patients & families {#patients}

This is a change in the SCN8A gene that is classified as benign/likely benign — not considered disease-causing, submitted by 8 submitters, and is linked to early-infantile DEE.

*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 | 4 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027299/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SCN8A](https://sugi.bio/atlas/gene/SCN8A/) |
| Protein change (HGVS p.) | p.Ter1981= |
| Coding change (HGVS c.) | c.5943GAG[1] |
| MANE Select transcript | [NM_001330260](https://www.ncbi.nlm.nih.gov/nuccore/NM_001330260) |
| dbSNP | [rs555793953](https://www.ncbi.nlm.nih.gov/snp/rs555793953/) |
| Variant type | Microsatellite |
| Location | chr12:51807429-51807431 (GRCh38) |
| ClinVar | [VCV196030](https://www.ncbi.nlm.nih.gov/clinvar/variation/196030/) |

**All HGVS expressions:** `LRG_1389:g.222472GAG[1]`, `LRG_1389t1:c.5943GAG[1]`, `LRG_1389t2:c.5943GAG[1]`, `NC_000012.11:g.52201213GAG[1]`, `NC_000012.12:g.51807429GAG[1]`, `NG_021180.3:g.222472GAG[1]`, `NM_001177984.3:c.5820GAG[1]`, `NM_001330260.2:c.5943GAG[1]`, `NM_001369788.1:c.5820GAG[1]`, `NM_014191.4:c.*3_*5del`, `NM_014191.4:c.*3_*5delGAG`, `NM_014191.4:c.5943GAG[1]`

## 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 9.395, GERP 2.82, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **stop-loss** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.189, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- CADD: **PHRED 7.039**. 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** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.693%** (afr) · FAF95 0.643% · FAF99 0.624% · 518/74,792 in the highest group · 595/1,604,900 alleles overall — rare (popmax 0.693%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.693% | 144 |
| Middle Eastern | 0.0826% | 1,210 |
| Admixed American | 0.0564% | 1,773 |
| Remaining individuals (not grpmax-eligible) | 0.045% | 2,222 |
| South Asian | 0.00334% | 29,950 |
| European (non-Finnish) | 0.000681% | 146,897 |

*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}

**SCN8A** population constraint: LOEUF 0.189, pLI 1, missense-Z 10.451. *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}


AlphaFold model confidence (whole protein): pLDDT 68.90, 16% of residues very-high.

**7 experimental structure(s)** (PDB): [25IH](https://www.rcsb.org/structure/25IH), [25II](https://www.rcsb.org/structure/25II), [25IJ](https://www.rcsb.org/structure/25IJ), [8FHD](https://www.rcsb.org/structure/8FHD), [8GZ1](https://www.rcsb.org/structure/8GZ1), [8GZ2](https://www.rcsb.org/structure/8GZ2).

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

*Describes the biological roles of SCN8A (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:** SCN8A's established molecular role includes voltage-gated sodium channel activity.


### Pathways affected {#pathways}

SCN8A participates in **2 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 |

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

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

**Biological process:** action potential, membrane depolarization during action potential.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-03.

**Submitter consensus:** conflicting (5 Benign, 3 Likely benign).

**Submission history:** 8 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2017-09-30 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2025-03-17 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2024-11-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2016-10-10 |
| Eurofins Ntd Llc (ga) | Likely benign | criteria provided, single submitter | clinical testing | 2014-11-25 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-02 |

## Associated conditions {#conditions}

[early-infantile DEE](https://sugi.bio/atlas/disease/early-infantile-dee/).

**Reported phenotype names (ClinVar):** Early-infantile DEE, not specified, not provided, Inborn genetic diseases, Ohtahara syndrome, Early infantile epileptic encephalopathy, Early infantile epileptic encephalopathy with suppression bursts, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related SCN8A variant pages (same residue, condition, or type): [SCN8A p.Ter1981LeuextTer?](/variant/scn8a-p-ter1981leuextter), [SCN8A p.Leu503_Ser504insTer](/variant/scn8a-p-leu503-ser504inster), [SCN8A p.Arg1968fs](/variant/scn8a-p-arg1968fs), [SCN8A p.Tyr1580del](/variant/scn8a-p-tyr1580del), [SCN8A c.2132-8_2132-5del](/variant/scn8a-c-2132-minus-8-2132-minus-5del), [SCN8A c.277-23TC[2]](/variant/scn8a-c-277-minus-23tc-2), [SCN8A c.277-10_277-7del](/variant/scn8a-c-277-minus-10-277-minus-7del), [SCN8A c.706+5_706+6del](/variant/scn8a-c-706-plus-5-706-plus-6del).

### 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 196030). 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.*