Is SCN5A p.Phe2003= (c.6009C>T) pathogenic?

SCN5A p.Phe2003= (c.6009C>T) is classified Likely benign in SCN5A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-01). Very rare (popmax 0.000176%, nfe); Associated with cardiac rhythm disease.

What condition is associated with SCN5A p.Phe2003= (c.6009C>T)?

SCN5A p.Phe2003= (c.6009C>T) is associated with cardiac rhythm disease (ClinVar).

How common is SCN5A p.Phe2003= (c.6009C>T) in the general population?

SCN5A p.Phe2003= (c.6009C>T) is very rare (popmax 0.000176%, nfe) (gnomAD).

SCN5A p.Phe2003=

c.6009C>T · rs755485335 · VCV2027673

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000176%, nfe)

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 0.33	GERP -3.1, phastCons 0.97
Overall
CADD	0.488	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000176% European (non-Finnish) · 2/1,139,138 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00013% 2/1,537,970 alleles · very rare

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.Phe2003=
Coding: c.6009C>T
MANE Select: NM_000335
dbSNP: rs755485335
Type: single nucleotide variant
Location: chr3:38550360 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.02 · 16 PDB
Residue 2003: 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.Phe2003Ile Uncertain significance ★★ ⚠ same residue
SCN5A p.Phe2003Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SCN5A p.Phe2003Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
SCN5A p.Phe2003Val Conflicting classifications of pathogenicity ★ ⚠ same residue
SCN5A p.Phe2003Cys Uncertain significance ★ ⚠ 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

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-phe2003 (accessed [today's date]).

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