Is SCN5A p.Pro823Ser (c.2467C>T) pathogenic?

SCN5A p.Pro823Ser (c.2467C>T) is classified Uncertain significance in SCN5A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-10). AlphaMissense: likely pathogenic (0.8212); Absent from gnomAD v4.1; Associated with cardiac rhythm disease.

What condition is associated with SCN5A p.Pro823Ser (c.2467C>T)?

SCN5A p.Pro823Ser (c.2467C>T) is associated with cardiac rhythm disease (ClinVar).

How common is SCN5A p.Pro823Ser (c.2467C>T) in the general population?

SCN5A p.Pro823Ser (c.2467C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN5A p.Pro823Ser (c.2467C>T)?

AlphaMissense predicts likely pathogenic (score 0.8212) — an in-silico prediction, not a clinical call.

SCN5A p.Pro823Ser

c.2467C>T · rs1303574728 · VCV3070399

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8212 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiac rhythm disease

Computational evidence

Protein change
AlphaMissense	0.8212	likely pathogenic
REVEL	0.86	moderately pathogenic-leaning
SaProt	LLR -10.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 4.6, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 4,720 bp · p 3.5e-11 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

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.Pro823Ser
Coding: c.2467C>T
MANE Select: NM_000335
dbSNP: rs1303574728
Type: single nucleotide variant
Location: chr3:38586011 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.02 · 16 PDB

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.Pro823Thr Uncertain significance ★★ ⚠ same residue
SCN5A p.Pro823= Likely benign ★★ 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
SCN5A c.611+1G>A 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-pro823ser (accessed [today's date]).

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