Is SCN5A p.Pro2004= (c.6012C>T) pathogenic?

SCN5A p.Pro2004= (c.6012C>T) is classified Likely benign in SCN5A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-09-04). Very rare (popmax 0.00228%, eas); Associated with cardiac rhythm disease.

What condition is associated with SCN5A p.Pro2004= (c.6012C>T)?

SCN5A p.Pro2004= (c.6012C>T) is associated with cardiac rhythm disease (ClinVar).

How common is SCN5A p.Pro2004= (c.6012C>T) in the general population?

SCN5A p.Pro2004= (c.6012C>T) is very rare (popmax 0.00228%, eas) (gnomAD).

SCN5A p.Pro2004=

c.6012C>T · rs2125824075 · VCV1633657

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00228%, eas)

Conditions

cardiac rhythm disease

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 -0.89	GERP -0.7
Overall
CADD	0.483	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00228% East Asian · 1/43,872 alleles

Overall 0.00013% 2/1,534,868 alleles · very rare exomes 2/1,385,604 · genomes 0/149,264 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00228%	43,872
European (non-Finnish)	8.79e-05%	1,137,790

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: SCN5A
Protein: p.Pro2004=
Coding: c.6012C>T
MANE Select: NM_000335
dbSNP: rs2125824075
Type: single nucleotide variant
Location: chr3:38550357 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.02 · 16 PDB
Residue 2004: a UniProt-annotated variant site (in lqt3 and brgda1; also found in patients with atrial fibrillation; results in channels with decreased peak and persistent current amplitudes; increased closed-state and slow inactivation; decelerated recovery from inactivation); a UniProt-annotated variant site (in brgda1 and lqt3); the 'disordered' region

Full SCN5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardiac rhythm disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SCN5A p.Pro2004Ser Uncertain significance ★★ ⚠ same residue
SCN5A p.Pro2004His Uncertain significance ★ ⚠ same residue
SCN5A p.Pro2004Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SCN5A c.1338+2T>A Pathogenic/Likely pathogenic ★★ same condition
SCN5A c.2263-2A>G Likely pathogenic ★★ same condition
SCN5A c.3508+1G>T Likely pathogenic ★★ same condition
SCN5A c.3837+1G>A Pathogenic ★★ same condition
SCN5A c.4242+1G>C 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/scn5a-p-pro2004 (accessed [today's date]).

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