Is SCN5A p.Val125Met (c.373G>A) pathogenic?

SCN5A p.Val125Met (c.373G>A) is classified Uncertain significance in SCN5A (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-08). AlphaMissense: likely benign (0.3312); Very rare (popmax 8.48e-05%, nfe); Associated with cardiac rhythm disease.

What condition is associated with SCN5A p.Val125Met (c.373G>A)?

SCN5A p.Val125Met (c.373G>A) is associated with cardiac rhythm disease (ClinVar).

How common is SCN5A p.Val125Met (c.373G>A) in the general population?

SCN5A p.Val125Met (c.373G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SCN5A p.Val125Met (c.373G>A)?

AlphaMissense predicts likely benign (score 0.3312) — an in-silico prediction, not a clinical call.

SCN5A p.Val125Met

c.373G>A · rs199473059 · VCV924003

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3312 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cardiac rhythm disease

Computational evidence

Protein change
AlphaMissense	0.3312	likely benign
REVEL	0.628	indeterminate
SaProt	LLR -10.50	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -0.23, phastCons 0.93
Regional constraint	o/e 0.63	unconstrained · MANE · 24 kb · p 1.4e-15 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,178,884 alleles

Overall 6.85e-05% 1/1,460,590 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.Val125Met
Coding: c.373G>A
MANE Select: NM_000335
dbSNP: rs199473059
Type: single nucleotide variant
Location: chr3:38630330 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.02 · 16 PDB
Residue 125: a UniProt-annotated variant site (in lqt3); an α-helix

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.Val125= Likely benign ★★ same residue
SCN5A p.Val125Leu Benign/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-val125met (accessed [today's date]).

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