# NM_001330260.2(SCN8A):c.2160G>A (p.Pro720=)

https://sugi.bio/variant/scn8a-p-pro720

## Summary

**SCN8A p.Pro720= (c.2160G>A)** is classified **Likely benign** in SCN8A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs967922373 · 2 submitters · 2 linked conditions · ultra-rare (popmax 0.0164%, mid)

## For patients & families {#patients}

This is a change in the SCN8A gene that is classified as likely benign — not considered disease-causing, submitted by 2 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 | [SCN8A](https://sugi.bio/atlas/gene/SCN8A/) |
| Protein change (HGVS p.) | p.Pro720= |
| Coding change (HGVS c.) | c.2160G>A |
| MANE Select transcript | [NM_001330260](https://www.ncbi.nlm.nih.gov/nuccore/NM_001330260) |
| dbSNP | [rs967922373](https://www.ncbi.nlm.nih.gov/snp/rs967922373/) |
| Variant type | single nucleotide variant |
| Location | chr12:51751383-51751383 (GRCh38) |
| ClinVar | [VCV530550](https://www.ncbi.nlm.nih.gov/clinvar/variation/530550/) |

**All HGVS expressions:** `LRG_1389:g.166426G>A`, `LRG_1389t1:c.2160G>A`, `LRG_1389t2:c.2160G>A`, `NC_000012.11:g.52145167G>A`, `NC_000012.12:g.51751383G>A`, `NG_021180.3:g.166426G>A`, `NM_001177984.3:c.2160G>A`, `NM_001330260.2:c.2160G>A`, `NM_001369788.1:c.2160G>A`, `NM_014191.4:c.2160G>A`

## 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 -6.44, GERP -3.74 — fast-evolving / accelerated position
- CADD: **PHRED 1.422**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.20 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0164%** (mid) · FAF95 0.00298% · FAF99 0.0018% · 1/6,080 in the highest group · 17/1,613,566 alleles overall — ultra-rare (popmax 0.0164%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0164% | 6,080 |
| East Asian | 0.00891% | 11,222 |
| Admixed American | 0.00167% | 59,996 |
| African / African-American | 0.00134% | 74,894 |
| European (non-Finnish) | 0.000848% | 117,974 |

*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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-10.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2017–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2017-07-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-10 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [early-infantile DEE](https://sugi.bio/atlas/disease/early-infantile-dee/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Early-infantile DEE, Early infantile epileptic encephalopathy, Early infantile epileptic encephalopathy with suppression bursts, Ohtahara syndrome.

## Similar variants {#similar}

Related SCN8A variant pages (same residue, condition, or type): [SCN8A p.Pro720Leu](/variant/scn8a-p-pro720leu), [SCN8A c.615-1G>A](/variant/scn8a-c-615-minus-1g-a), [SCN8A p.Arg1872Gln](/variant/scn8a-p-arg1872gln), [SCN8A p.Asn418Asp](/variant/scn8a-p-asn418asp), [SCN8A p.Glu1218Lys](/variant/scn8a-p-glu1218lys), [SCN8A p.Ile1631Thr](/variant/scn8a-p-ile1631thr), [SCN8A p.Ser845Cys](/variant/scn8a-p-ser845cys), [SCN8A p.Ser845Phe](/variant/scn8a-p-ser845phe).

### 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 2026-07-14); 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 530550). 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.*