Is SCN4A p.Ser262= (c.786C>T) pathogenic?

SCN4A p.Ser262= (c.786C>T) is classified Conflicting classifications of pathogenicity in SCN4A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-16). Ultra-rare (popmax 0.0183%, amr); Associated with hyperkalemic periodic paralysis.

What condition is associated with SCN4A p.Ser262= (c.786C>T)?

SCN4A p.Ser262= (c.786C>T) is associated with hyperkalemic periodic paralysis (ClinVar).

How common is SCN4A p.Ser262= (c.786C>T) in the general population?

SCN4A p.Ser262= (c.786C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

How is Hyperkalemic periodic paralysis inherited?

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

SCN4A p.Ser262=

c.786C>T · rs746749167 · VCV1157129

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

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 -4.3	GERP -4.8
Overall
CADD	5.387	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/60,000 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.0013% 21/1,613,716 alleles · ultra-rare exomes 19/1,461,570 · genomes 2/152,146 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,455
Remaining individualsnot grpmax-eligible	0.0032%	31,240
South Asian	0.0011%	91,078
European (non-Finnish)	0.000593%	168,533

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.Ser262=
Coding: c.786C>T
MANE Select: NM_000334
dbSNP: rs746749167
Type: single nucleotide variant
Location: chr17:63968273 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.09 · 3 PDB
Residue 262: an α-helix

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 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
SCN4A p.Arg672Gly Pathogenic ★★ same condition
SCN4A p.Arg672His 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-ser262 (accessed [today's date]).

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