Is SCN4A p.Pro153= (c.459G>A) pathogenic?

SCN4A p.Pro153= (c.459G>A) is classified Likely benign in SCN4A (ClinVar, Single submitter, 2 submitters; last evaluated 2025-09-02). Very rare (popmax 0.004%, afr); Associated with hyperkalemic periodic paralysis.

What condition is associated with SCN4A p.Pro153= (c.459G>A)?

SCN4A p.Pro153= (c.459G>A) is associated with hyperkalemic periodic paralysis (ClinVar).

How common is SCN4A p.Pro153= (c.459G>A) in the general population?

SCN4A p.Pro153= (c.459G>A) is very rare (popmax 0.004%, afr) (gnomAD).

How is Hyperkalemic periodic paralysis inherited?

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

SCN4A p.Pro153=

c.459G>A · rs201227173 · VCV703462

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

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 -4.6
Overall
CADD	10.82	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/75,008 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00254% 41/1,613,074 alleles · very rare exomes 32/1,460,878 · genomes 9/152,196 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	25,003
European (non-Finnish)	0.00305%	32,762
South Asian	0.0022%	45,435

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.Pro153=
Coding: c.459G>A
MANE Select: NM_000334
dbSNP: rs201227173
Type: single nucleotide variant
Location: chr17:63972159 (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.Pro153Leu 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-pro153 (accessed [today's date]).

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