Is SCN8A p.Ser217Pro (c.649T>C) pathogenic?

SCN8A p.Ser217Pro (c.649T>C) is classified Pathogenic in SCN8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-28). AlphaMissense: likely pathogenic (0.9764); Absent from gnomAD v4.1.

How common is SCN8A p.Ser217Pro (c.649T>C) in the general population?

SCN8A p.Ser217Pro (c.649T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN8A p.Ser217Pro (c.649T>C)?

AlphaMissense predicts likely pathogenic (score 0.9764) — an in-silico prediction, not a clinical call.

SCN8A p.Ser217Pro

c.649T>C · rs1064794715 · VCV420809

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9764 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9764	likely pathogenic ✓ concordant with ClinVar
REVEL	0.972	strongly pathogenic-leaning
SaProt	LLR -10.65	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 37 kb · p 1e-36 · regional, not allelic
Overall
CADD	22.1	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.Ser217Pro
Coding: c.649T>C
MANE Select: NM_001330260 · reported on NM_014191
dbSNP: rs1064794715
Type: single nucleotide variant
Location: chr12:51688792 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.90 · 7 PDB
Residue 217: an α-helix

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

Similar variants

SCN8A p.Ser217= Likely benign ★★ same residue
SCN8A c.615-1G>A Pathogenic ★★★ same type
SCN8A p.Arg1872Gln Pathogenic ★★★ ⚠ same type
SCN8A p.Asn1318Ser Likely pathogenic ★★★ same type
SCN8A p.Asn418Asp Likely pathogenic ★★★ same type
SCN8A p.Glu1218Lys Pathogenic ★★★ same type
SCN8A p.Ile1631Thr Likely pathogenic ★★★ same type
SCN8A p.Ser845Cys Likely pathogenic ★★★ ⚠ same type

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-ser217pro (accessed [today's date]).

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