Is SCN4A p.Ser296= (c.888C>T) pathogenic?

SCN4A p.Ser296= (c.888C>T) is classified Conflicting classifications of pathogenicity in SCN4A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-11-28). Very rare (popmax 8.48e-05%, nfe); Associated with hyperkalemic periodic paralysis.

What condition is associated with SCN4A p.Ser296= (c.888C>T)?

SCN4A p.Ser296= (c.888C>T) is associated with hyperkalemic periodic paralysis (ClinVar).

How common is SCN4A p.Ser296= (c.888C>T) in the general population?

SCN4A p.Ser296= (c.888C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Hyperkalemic periodic paralysis inherited?

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

SCN4A p.Ser296=

c.888C>T · rs1290597719 · VCV1807334

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

hyperkalemic periodic paralysis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.71	GERP -1.3, phastCons 0.96
Overall
CADD	4.308	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,890 alleles

Overall 6.2e-05% 1/1,613,974 alleles · very rare exomes 1/1,461,710 · genomes 0/152,264 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SCN4A
Protein: p.Ser296=
Coding: c.888C>T
MANE Select: NM_000334
dbSNP: rs1290597719
Type: single nucleotide variant
Location: chr17:63968171 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.09 · 3 PDB

Full SCN4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyperkalemic periodic paralysis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hyperkalemic periodic paralysis (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

SCN4A p.Ser296Ile Uncertain significance ★ ⚠ same residue
SCN4A p.Ser296_Tyr301dup Uncertain significance ★★ same residue
SCN4A c.1037-1G>A Pathogenic/Likely pathogenic ★★ same condition
SCN4A p.Arg1132Gln Pathogenic ★★ same condition
SCN4A p.Arg222Gln Pathogenic/Likely pathogenic ★★ same condition
SCN4A p.Arg222Trp Pathogenic/Likely pathogenic ★★ same condition
SCN4A p.Arg669His Pathogenic ★★ same condition
SCN4A p.Arg672Cys 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/scn4a-p-ser296 (accessed [today's date]).

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