Is SCN1B p.Val91= (c.273G>A) pathogenic?

SCN1B p.Val91= (c.273G>A) is classified Conflicting classifications of pathogenicity in SCN1B (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-30). Ultra-rare (popmax 0.0183%, amr); Associated with Brugada syndrome 5.

What condition is associated with SCN1B p.Val91= (c.273G>A)?

SCN1B p.Val91= (c.273G>A) is associated with Brugada syndrome 5 (ClinVar).

How common is SCN1B p.Val91= (c.273G>A) in the general population?

SCN1B p.Val91= (c.273G>A) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

How is Brugada syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

SCN1B p.Val91=

c.273G>A · rs16969926 · VCV282734

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Conditions

Brugada syndrome 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -0.57, phastCons 1
Overall
CADD	7.572	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/60,002 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.000805% 13/1,613,956 alleles · ultra-rare exomes 11/1,461,832 · genomes 2/152,124 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,455
South Asian	0.0011%	91,078
European (non-Finnish)	8.47e-05%	1,179,981

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: SCN1B
Protein: p.Val91=
Coding: c.273G>A
MANE Select: NM_001037
dbSNP: rs16969926
Type: single nucleotide variant
Location: chr19:35033564 (GRCh38)
Gene constraint: LOEUF 0.71 · pLI 0.20 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.90 · 39 PDB
Residue 91: a β-strand; the ig-like c2-type domain

Full SCN1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Brugada syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Brugada syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

SCN1B c.449-2A>G Pathogenic ★★★ same condition
SCN1B c.449-1G>T Likely pathogenic ★★ same condition
SCN1B p.Arg85Cys Pathogenic/Likely pathogenic ★★ same condition
SCN1B p.Arg85His Pathogenic/Likely pathogenic ★★ ⚠ same condition
SCN1B p.Val158Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
SCN1B c.448+100G>T Uncertain significance ★★ same condition
SCN1B c.448+103C>T Uncertain significance ★★ same condition
SCN1B c.448+10G>C 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/scn1b-p-val91 (accessed [today's date]).

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