Is SCN4A p.Arg55= (c.163C>A) pathogenic?

SCN4A p.Arg55= (c.163C>A) is classified Likely benign in SCN4A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-01). Very rare (popmax 0.0022%, sas); Associated with hyperkalemic periodic paralysis.

What condition is associated with SCN4A p.Arg55= (c.163C>A)?

SCN4A p.Arg55= (c.163C>A) is associated with hyperkalemic periodic paralysis (ClinVar).

How common is SCN4A p.Arg55= (c.163C>A) in the general population?

SCN4A p.Arg55= (c.163C>A) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Hyperkalemic periodic paralysis inherited?

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

SCN4A p.Arg55=

c.163C>A · rs754070476 · VCV727425

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

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 5.2	GERP -1.4, phastCons 1
Overall
CADD	11.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,002 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000479% 7/1,461,358 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,236
South Asiangrpmax	0.0022%	45,501
European (non-Finnish)	0.000254%	393,239

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg55=
Coding: c.163C>A
MANE Select: NM_000334
dbSNP: rs754070476
Type: single nucleotide variant
Location: chr17:63972679 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.09 · 3 PDB
Residue 55: the 'disordered' region

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.Arg55Gln 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
SCN4A p.Arg672Gly 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-arg55 (accessed [today's date]).

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