# NM_014191.4(SCN8A):c.630T>C (p.Phe210=)

https://sugi.bio/variant/scn8a-p-phe210

## Summary

**SCN8A p.Phe210= (c.630T>C)** is classified **Conflicting classifications of pathogenicity** in SCN8A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-05-17). Very rare (popmax 8.48e-05%, nfe); Associated with early-infantile DEE.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs2138716083 · 2 submitters · 1 linked condition · very rare (popmax 8.48e-05%, 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.Phe210= |
| Coding change (HGVS c.) | c.630T>C |
| MANE Select transcript | [NM_001330260](https://www.ncbi.nlm.nih.gov/nuccore/NM_001330260) (variant reported on NM_014191) |
| dbSNP | [rs2138716083](https://www.ncbi.nlm.nih.gov/snp/rs2138716083/) |
| Variant type | single nucleotide variant |
| Location | chr12:51688773-51688773 (GRCh38) |
| ClinVar | [VCV1153326](https://www.ncbi.nlm.nih.gov/clinvar/variation/1153326/) |

**All HGVS expressions:** `LRG_1389:g.103816T>C`, `LRG_1389t1:c.615-232T>C`, `LRG_1389t2:c.630T>C`, `NC_000012.11:g.52082557T>C`, `NC_000012.12:g.51688773T>C`, `NG_021180.3:g.103816T>C`, `NM_001177984.3:c.630T>C`, `NM_001330260.2:c.615-232T>C`, `NM_001369788.1:c.615-232T>C`, `NM_014191.4:c.630T>C`

## 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 6.219, GERP 1.87, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 22.2**. 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 (T>A, Δ0.24 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.*
- Pangolin: Δ**0.20** (gain), gain 0.20 / loss 0.00. SpliceAI below 0.2. 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 **8.48e-05%** (nfe) · 1/1,179,720 in the highest group · 1/1,613,840 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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}

Residue **210** lies in a UniProt-annotated variant site (in dee13); a β-strand.

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 2022-05-17.

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

**Submission history:** 2 submissions (2020–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2020-02-01 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related SCN8A variant pages (same residue, condition, or type): [SCN8A p.Phe210Leu](/variant/scn8a-p-phe210leu), [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 2026-10-14); 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 1153326). 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.*