Is SCN8A p.Arg99Ser (c.297A>C) pathogenic?

SCN8A p.Arg99Ser (c.297A>C) is classified Uncertain significance in SCN8A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-11). AlphaMissense: likely pathogenic (0.6947); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 13.

What condition is associated with SCN8A p.Arg99Ser (c.297A>C)?

SCN8A p.Arg99Ser (c.297A>C) is associated with developmental and epileptic encephalopathy, 13, early-infantile DEE (ClinVar).

How common is SCN8A p.Arg99Ser (c.297A>C) in the general population?

SCN8A p.Arg99Ser (c.297A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN8A p.Arg99Ser (c.297A>C)?

AlphaMissense predicts likely pathogenic (score 0.6947) — an in-silico prediction, not a clinical call.

SCN8A p.Arg99Ser

Q: How is Non-specific early-onset epileptic encephalopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.297A>C · rs1565885985 · VCV633702

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6947 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

developmental and epileptic encephalopathy, 13

Computational evidence

Protein change
AlphaMissense	0.6947	likely pathogenic
REVEL	0.526	indeterminate
SaProt	LLR -7.06	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.28	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 9.4	GERP 0.74, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 37 kb · p 1e-36 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SCN8A
Protein: p.Arg99Ser
Coding: c.297A>C
MANE Select: NM_001330260
dbSNP: rs1565885985
Type: single nucleotide variant
Location: chr12:51684194 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.90 · 7 PDB

Full SCN8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 13 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: early-infantile DEE

For Non-specific early-onset epileptic encephalopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Infancy, Neonatal

Similar variants

SCN8A p.Arg99Thr Uncertain significance ★ ⚠ same residue
SCN8A c.615-1G>A Pathogenic ★★★ same condition
SCN8A p.Arg1872Gln Pathogenic ★★★ ⚠ same condition
SCN8A p.Asn1318Ser Likely pathogenic ★★★ same condition
SCN8A p.Asn418Asp Likely pathogenic ★★★ same condition
SCN8A p.Glu1218Lys Pathogenic ★★★ same condition
SCN8A p.Ile1631Thr Likely pathogenic ★★★ same condition
SCN8A p.Ser845Cys Likely pathogenic ★★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/scn8a-p-arg99ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown