Is SCN5A p.Phe2003Val (c.6007T>G) pathogenic?

SCN5A p.Phe2003Val (c.6007T>G) is classified Conflicting classifications of pathogenicity in SCN5A (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.0674); Very rare (popmax 0.000703%, nfe); Associated with cardiac rhythm disease.

What condition is associated with SCN5A p.Phe2003Val (c.6007T>G)?

SCN5A p.Phe2003Val (c.6007T>G) is associated with cardiac rhythm disease, progressive familial heart block, type 1A, Brugada syndrome 1 (ClinVar).

How common is SCN5A p.Phe2003Val (c.6007T>G) in the general population?

SCN5A p.Phe2003Val (c.6007T>G) is very rare (popmax 0.000703%, nfe) (gnomAD).

What do computational predictors say about SCN5A p.Phe2003Val (c.6007T>G)?

AlphaMissense predicts likely benign (score 0.0674) — an in-silico prediction, not a clinical call.

SCN5A p.Phe2003Val

c.6007T>G · rs41311117 · VCV68022

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0674 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000703%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cardiac rhythm disease

Computational evidence

Protein change
AlphaMissense	0.0674	likely benign
REVEL	0.566	indeterminate
SaProt	LLR -5.21	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.53, phastCons 0.99
Regional constraint	o/e 0.98	unconstrained · MANE · 348 bp · p 0.81 · regional, not allelic
Overall
CADD	7.036	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F2004V vs ClinVar F2003V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000703% European (non-Finnish) · 8/1,137,440 alleles

Filtering AF 0.000303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000219%

Overall 0.00267% 41/1,533,934 alleles · very rare exomes 36/1,385,538 · genomes 5/148,396 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.118%	848
Remaining individualsnot grpmax-eligible	0.00678%	14,747
European (non-Finnish)grpmax	0.000703%	142,180

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe2003Val
Coding: c.6007T>G
MANE Select: NM_000335
dbSNP: rs41311117
Type: single nucleotide variant
Location: chr3:38550362 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.02 · 16 PDB
Residue 2004 UniProt numbering: 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

Also linked: progressive familial heart block, type 1A Brugada syndrome 1 dilated cardiomyopathy 1E ventricular fibrillation, paroxysmal familial, type 1 long QT syndrome 3 familial long QT syndrome sick sinus syndrome 1

Similar variants

SCN5A p.Phe2003Ile Uncertain significance ★★ ⚠ same residue
SCN5A p.Phe2003= Likely benign ★★ same residue
SCN5A p.Phe2003Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SCN5A p.Phe2003Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
SCN5A p.Phe2003Cys Uncertain significance ★ ⚠ same residue
SCN5A c.1140+1G>A Pathogenic/Likely pathogenic ★★ same condition
SCN5A c.1338+2T>A Pathogenic/Likely pathogenic ★★ same condition
SCN5A c.2263-2A>G 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-phe2003val (accessed [today's date]).

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