Is SCN2B p.Ser64Phe (c.191C>T) pathogenic?

SCN2B p.Ser64Phe (c.191C>T) is classified Conflicting classifications of pathogenicity in SCN2B (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-11-16). AlphaMissense: likely pathogenic (0.7658); Ultra-rare (popmax 0.03%, amr); Associated with Cardiovascular phenotype.

What condition is associated with SCN2B p.Ser64Phe (c.191C>T)?

SCN2B p.Ser64Phe (c.191C>T) is associated with Cardiovascular phenotype, atrial fibrillation, familial, 14 (ClinVar).

How common is SCN2B p.Ser64Phe (c.191C>T) in the general population?

SCN2B p.Ser64Phe (c.191C>T) is ultra-rare (popmax 0.03%, amr) (gnomAD).

What do computational predictors say about SCN2B p.Ser64Phe (c.191C>T)?

AlphaMissense predicts likely pathogenic (score 0.7658) — an in-silico prediction, not a clinical call.

SCN2B p.Ser64Phe

c.191C>T · rs764221630 · VCV2496755

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7658 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.7658	likely pathogenic
REVEL	0.37	indeterminate
SaProt	LLR -7.74	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 9,541 bp · p 0.14 · regional, not allelic
Overall
CADD	28.5	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 0.03% Admixed American · 18/60,012 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00167% 27/1,614,098 alleles · ultra-rare exomes 24/1,461,864 · genomes 3/152,234 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,334
European (non-Finnish)	0.000763%	131,116

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: SCN2B
Protein: p.Ser64Phe
Coding: c.191C>T
MANE Select: NM_004588
dbSNP: rs764221630
Type: single nucleotide variant
Location: chr11:118168631 (GRCh38)
Gene constraint: LOEUF 1.15 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.03 · 35 PDB
Residue 64: a β-strand; the ig-like c2-type domain

Full SCN2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: atrial fibrillation, familial, 14

Similar variants

SCN2B p.Ala171Pro Uncertain significance ★★ ⚠ same condition
SCN2B p.Arg135Cys Uncertain significance ★★ ⚠ same condition
SCN2B p.Arg137His Uncertain significance ★★ ⚠ same condition
SCN2B p.Arg154Gln Uncertain significance ★★ ⚠ same condition
SCN2B p.Arg185Thr Uncertain significance ★★ ⚠ same condition
SCN2B p.Arg84Cys Uncertain significance ★★ ⚠ same condition
SCN2B p.Arg98Cys Uncertain significance ★★ ⚠ same condition
SCN2B p.Arg98Gly 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/scn2b-p-ser64phe (accessed [today's date]).

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