Is SCN4B p.Trp14Cys (c.42G>T) pathogenic?

SCN4B p.Trp14Cys (c.42G>T) is classified Uncertain significance in SCN4B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-24). AlphaMissense: ambiguous (0.3976); Very rare (popmax 0.000424%, nfe); Associated with long QT syndrome 10.

What condition is associated with SCN4B p.Trp14Cys (c.42G>T)?

SCN4B p.Trp14Cys (c.42G>T) is associated with long QT syndrome 10 (ClinVar).

How common is SCN4B p.Trp14Cys (c.42G>T) in the general population?

SCN4B p.Trp14Cys (c.42G>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

How is Hereditary atrial fibrillation inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SCN4B p.Trp14Cys (c.42G>T)?

AlphaMissense predicts ambiguous (score 0.3976) — an in-silico prediction, not a clinical call.

SCN4B p.Trp14Cys

c.42G>T · rs1555098880 · VCV2988268

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3976 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

long QT syndrome 10

Computational evidence

Protein change
AlphaMissense	0.3976	ambiguous
REVEL	0.616	indeterminate
SaProt	LLR -7.01	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.33 · regional, not allelic
Overall
CADD	26.7	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 0.000424% European (non-Finnish) · 5/1,179,306 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,612,548 alleles · very rare exomes 4/1,460,318 · genomes 1/152,230 · joint denominator

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: SCN4B
Protein: p.Trp14Cys
Coding: c.42G>T
MANE Select: NM_174934
dbSNP: rs1555098880
Type: single nucleotide variant
Location: chr11:118152632 (GRCh38)
Gene constraint: LOEUF 1.324 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.91 · 5 PDB

Full SCN4B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

long QT syndrome 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary atrial fibrillation (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

SCN4B p.Trp14Gly Uncertain significance ★★ ⚠ same residue
SCN4B c.234+1G>A Uncertain significance ★★ same condition
SCN4B c.463+3A>T Uncertain significance ★★ same condition
SCN4B c.594-2A>G Uncertain significance ★★ same condition
SCN4B c.61+1G>A Uncertain significance ★★ same condition
SCN4B c.62-1G>A Uncertain significance ★★ same condition
SCN4B c.*961A>G Uncertain significance ★★ same condition
SCN4B p.Ala12Thr Uncertain significance ★★ ⚠ 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/scn4b-p-trp14cys (accessed [today's date]).

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