# NM_001330260.2(SCN8A):c.1995A>G (p.Pro665=)

https://sugi.bio/variant/scn8a-p-pro665

## Summary

**SCN8A p.Pro665= (c.1995A>G)** is classified **Conflicting classifications of pathogenicity** in SCN8A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-03-01). Very rare (popmax 0.000509%, nfe); Associated with early-infantile DEE.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1231370273 · 2 submitters · 1 linked condition · very rare (popmax 0.000509%, nfe)

## For patients & families {#patients}

This is a change in the SCN8A gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 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.Pro665= |
| Coding change (HGVS c.) | c.1995A>G |
| MANE Select transcript | [NM_001330260](https://www.ncbi.nlm.nih.gov/nuccore/NM_001330260) |
| dbSNP | [rs1231370273](https://www.ncbi.nlm.nih.gov/snp/rs1231370273/) |
| Variant type | single nucleotide variant |
| Location | chr12:51721905-51721905 (GRCh38) |
| ClinVar | [VCV1213499](https://www.ncbi.nlm.nih.gov/clinvar/variation/1213499/) |

**All HGVS expressions:** `LRG_1389:g.136948A>G`, `LRG_1389t1:c.1995A>G`, `LRG_1389t2:c.1995A>G`, `NC_000012.11:g.52115689A>G`, `NC_000012.12:g.51721905A>G`, `NG_021180.3:g.136948A>G`, `NM_001177984.3:c.1995A>G`, `NM_001330260.2:c.1995A>G`, `NM_001369788.1:c.1995A>G`, `NM_014191.4:c.1995A>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.22) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 3.89, GERP 0.706, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.24**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.22**, acceptor gain **0.00**, donor gain **0.17**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.22**, acceptor gain **0.00**, donor gain **0.17**.
- Pangolin: Δ**0.24** (loss), gain 0.20 / loss 0.24. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000509%** (nfe) · FAF95 0.000183% · FAF99 0.00012% · 6/1,179,774 in the highest group · 7/1,599,844 alleles overall — very rare (popmax 0.000509%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,382 |
| European (non-Finnish) (grpmax) | 0.000509% | 196,629 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2023-03-01.

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

**Submission history:** 2 submissions (2019–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2019-06-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-03-01 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related SCN8A variant pages (same residue, condition, or type): [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), [SCN8A p.Tyr401His](/variant/scn8a-p-tyr401his).

### 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 1213499). 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.*