Is SCN10A p.Pro548= (c.1644C>T) pathogenic?

SCN10A p.Pro548= (c.1644C>T) is classified Likely benign in SCN10A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-22). Ultra-rare (popmax 0.012%, afr); Associated with Cardiovascular phenotype.

What condition is associated with SCN10A p.Pro548= (c.1644C>T)?

SCN10A p.Pro548= (c.1644C>T) is associated with Cardiovascular phenotype, Brugada syndrome (ClinVar).

How common is SCN10A p.Pro548= (c.1644C>T) in the general population?

SCN10A p.Pro548= (c.1644C>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

SCN10A p.Pro548=

c.1644C>T · rs753205934 · VCV1081488

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Conditions

Cardiovascular phenotype

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 0.27	GERP -4.3, phastCons 0.94
Overall
CADD	7.371	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/74,836 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00062% 10/1,612,936 alleles · ultra-rare exomes 5/1,460,852 · genomes 5/152,084 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,315
European (non-Finnish)	8.48e-05%	1,179,585

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: SCN10A
Protein: p.Pro548=
Coding: c.1644C>T
MANE Select: NM_006514
dbSNP: rs753205934
Type: single nucleotide variant
Location: chr3:38752330 (GRCh38)
Gene constraint: LOEUF 1.058 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.06 · 8 PDB
Residue 548: the 'disordered' region

Full SCN10A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Brugada syndrome

Similar variants

SCN10A p.Pro548Leu Uncertain significance ★★ ⚠ same residue
SCN10A c.1093-3C>A Uncertain significance ★★ same condition
SCN10A c.2106+1G>A Uncertain significance ★★ same condition
SCN10A c.270+2T>C Uncertain significance ★★ same condition
SCN10A c.271-2A>G Uncertain significance ★★ same condition
SCN10A c.3804+1G>A Uncertain significance ★★ same condition
SCN10A c.3804+5G>C Uncertain significance ★★ same condition
SCN10A c.4089+1G>A Uncertain significance ★★ 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/scn10a-p-pro548 (accessed [today's date]).

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