Is SCN4A p.Pro520= (c.1560G>A) pathogenic?

SCN4A p.Pro520= (c.1560G>A) is classified Likely benign in SCN4A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-19). Very rare (popmax 0.00336%, amr); Associated with congenital myasthenic syndrome 16.

What condition is associated with SCN4A p.Pro520= (c.1560G>A)?

SCN4A p.Pro520= (c.1560G>A) is associated with congenital myasthenic syndrome 16, paramyotonia congenita of Von Eulenburg, hyperkalemic periodic paralysis (ClinVar).

How common is SCN4A p.Pro520= (c.1560G>A) in the general population?

SCN4A p.Pro520= (c.1560G>A) is very rare (popmax 0.00336%, amr) (gnomAD).

SCN4A p.Pro520=

c.1560G>A · rs373819078 · VCV1084495

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00336%, amr)

Conditions

congenital myasthenic syndrome 16

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -12	GERP -2.6
Overall
CADD	0.672	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00336% Admixed American · 2/59,446 alleles

Filtering AF 0.00197% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00169%

Overall 0.00231% 37/1,601,724 alleles · very rare exomes 35/1,449,492 · genomes 2/152,232 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00336%	29,723
European (non-Finnish)	0.00273%	36,684
Finnishnot grpmax-eligible	0.00162%	61,730
Remaining individualsnot grpmax-eligible	0.00161%	61,946
South Asian	0.00111%	89,828

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.Pro520=
Coding: c.1560G>A
MANE Select: NM_000334
dbSNP: rs373819078
Type: single nucleotide variant
Location: chr17:63963718 (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 hypokalemic periodic paralysis, type 1

Similar variants

SCN4A p.Pro520Arg Uncertain significance ★★ ⚠ same residue
SCN4A p.Pro520Leu Uncertain significance ★★ ⚠ 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-pro520 (accessed [today's date]).

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