Is SCN5A p.Trp1439Arg (c.4315T>A) pathogenic?

SCN5A p.Trp1439Arg (c.4315T>A) is classified Uncertain significance in SCN5A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely pathogenic (0.9067); Absent from gnomAD v4.1.

How common is SCN5A p.Trp1439Arg (c.4315T>A) in the general population?

SCN5A p.Trp1439Arg (c.4315T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN5A p.Trp1439Arg (c.4315T>A)?

AlphaMissense predicts likely pathogenic (score 0.9067) — an in-silico prediction, not a clinical call.

SCN5A p.Trp1439Arg

c.4315T>A · rs2061164027 · VCV1928565

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9067 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9067	likely pathogenic
REVEL	0.659	pathogenic-leaning
SaProt	LLR -2.80	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 15 kb · p 2e-12 · regional, not allelic
Overall
CADD	23.1	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 W1440R vs ClinVar W1439R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SCN5A
Protein: p.Trp1439Arg
Coding: c.4315T>A
MANE Select: NM_000335
dbSNP: rs2061164027
Type: single nucleotide variant
Location: chr3:38556560 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.02 · 16 PDB
Residue 1440 UniProt numbering: a turn

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

Similar variants

SCN5A p.Trp1439Ter Pathogenic ★ same residue
SCN5A p.Trp1439fs Pathogenic same residue
SCN5A c.1140+1G>A Pathogenic/Likely pathogenic ★★ same type
SCN5A c.1338+2T>A Pathogenic/Likely pathogenic ★★ same type
SCN5A c.1891-1G>A Pathogenic/Likely pathogenic ★★ same type
SCN5A c.2263-2A>G Likely pathogenic ★★ same type
SCN5A c.2437-1G>C Likely pathogenic ★★ same type
SCN5A c.273+1G>A Likely pathogenic ★★ same type

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-trp1439arg (accessed [today's date]).

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