Is SCN4A p.Arg669Cys (c.2005C>T) pathogenic?

SCN4A p.Arg669Cys (c.2005C>T) is classified Conflicting classifications of pathogenicity in SCN4A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-01). AlphaMissense: likely pathogenic (0.9971); Very rare (popmax 0.000424%, nfe); Associated with hyperkalemic periodic paralysis.

What condition is associated with SCN4A p.Arg669Cys (c.2005C>T)?

SCN4A p.Arg669Cys (c.2005C>T) is associated with hyperkalemic periodic paralysis (ClinVar).

How common is SCN4A p.Arg669Cys (c.2005C>T) in the general population?

SCN4A p.Arg669Cys (c.2005C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

How is Hyperkalemic periodic paralysis inherited?

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

What do computational predictors say about SCN4A p.Arg669Cys (c.2005C>T)?

AlphaMissense predicts likely pathogenic (score 0.9971) — an in-silico prediction, not a clinical call.

SCN4A p.Arg669Cys

c.2005C>T · rs897448432 · VCV843445

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9971 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperkalemic periodic paralysis

Computational evidence

Protein change
AlphaMissense	0.9971	likely pathogenic · top 7% in SCN4A
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -14.59	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.24	donor gain · deltas
Pangolin	Δ0.23	loss · gain 0.13 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 32 kb · p 7.8e-08 · regional, not allelic
Overall
CADD	34.0	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

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,470 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,352 alleles · very rare exomes 5/1,461,146 · genomes 0/152,206 · 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.Arg669Cys
Coding: c.2005C>T
MANE Select: NM_000334
dbSNP: rs897448432
Type: single nucleotide variant
Location: chr17:63959279 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.09 · 3 PDB
Residue 669: a UniProt-annotated variant site (in hokpp2); 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 p.Arg669His Pathogenic ★★ 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.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-arg669cys (accessed [today's date]).

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