Is SCN4A p.Pro520Arg (c.1559C>G) pathogenic?

SCN4A p.Pro520Arg (c.1559C>G) is classified Uncertain significance in SCN4A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-09-02). AlphaMissense: likely benign (0.091); Ultra-rare (popmax 0.0181%, eas); Associated with congenital myasthenic syndrome 16.

What condition is associated with SCN4A p.Pro520Arg (c.1559C>G)?

SCN4A p.Pro520Arg (c.1559C>G) is associated with congenital myasthenic syndrome 16, paramyotonia congenita of Von Eulenburg, hyperkalemic periodic paralysis (ClinVar).

How common is SCN4A p.Pro520Arg (c.1559C>G) in the general population?

SCN4A p.Pro520Arg (c.1559C>G) is ultra-rare (popmax 0.0181%, eas) (gnomAD).

What do computational predictors say about SCN4A p.Pro520Arg (c.1559C>G)?

AlphaMissense predicts likely benign (score 0.091) — an in-silico prediction, not a clinical call.

SCN4A p.Pro520Arg

c.1559C>G · rs753391449 · VCV566952

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.091 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0181%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital myasthenic syndrome 16

Computational evidence

Protein change
AlphaMissense	0.091	likely benign
REVEL	0.426	indeterminate
SaProt	LLR -4.35	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 32 kb · p 7.8e-08 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0181% East Asian · 8/44,220 alleles

Filtering AF 0.00895% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00649%

Overall 0.000621% 9/1,448,814 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0181%	5,527
Remaining individualsnot grpmax-eligible	0.00161%	61,934

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.Pro520Arg
Coding: c.1559C>G
MANE Select: NM_000334
dbSNP: rs753391449
Type: single nucleotide variant
Location: chr17:63963719 (GRCh38)
Gene constraint: LOEUF 0.628 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.09 · 3 PDB
Residue 520: the 'disordered' region

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

Disease context

congenital myasthenic syndrome 16 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: paramyotonia congenita of Von Eulenburg hyperkalemic periodic paralysis hypokalemic periodic paralysis, type 2 potassium-aggravated myotonia

Similar variants

SCN4A p.Pro520Leu Uncertain significance ★★ ⚠ same residue
SCN4A p.Pro520= Likely benign ★★ same residue
SCN4A p.Pro520Ser Uncertain significance ★ ⚠ same residue
SCN4A p.Pro520Gln 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

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-pro520arg (accessed [today's date]).

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