Is SCN2B p.Pro49Ser (c.145C>T) pathogenic?

SCN2B p.Pro49Ser (c.145C>T) is classified Uncertain significance in SCN2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-30). AlphaMissense: likely benign (0.084); Very rare (popmax 0.00266%, afr); Associated with atrial fibrillation, familial, 14.

What condition is associated with SCN2B p.Pro49Ser (c.145C>T)?

SCN2B p.Pro49Ser (c.145C>T) is associated with atrial fibrillation, familial, 14 (ClinVar).

How common is SCN2B p.Pro49Ser (c.145C>T) in the general population?

SCN2B p.Pro49Ser (c.145C>T) is very rare (popmax 0.00266%, afr) (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 SCN2B p.Pro49Ser (c.145C>T)?

AlphaMissense predicts likely benign (score 0.084) — an in-silico prediction, not a clinical call.

SCN2B p.Pro49Ser

c.145C>T · rs2497601597 · VCV2500083

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.084 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atrial fibrillation, familial, 14

Computational evidence

Protein change
AlphaMissense	0.084	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -7.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.45	GERP -3.9
Regional constraint	o/e 0.91	unconstrained · MANE · 9,541 bp · p 0.14 · regional, not allelic
Overall
CADD	1.265	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00266% African / African-American · 2/75,064 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000137% 2/1,461,880 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: SCN2B
Protein: p.Pro49Ser
Coding: c.145C>T
MANE Select: NM_004588
dbSNP: rs2497601597
Type: single nucleotide variant
Location: chr11:118168677 (GRCh38)
Gene constraint: LOEUF 1.15 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.03 · 35 PDB
Residue 49: the ig-like c2-type domain

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

Disease context

atrial fibrillation, familial, 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary atrial fibrillation (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

SCN2B p.Pro49Leu Likely benign ★ same residue
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

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-pro49ser (accessed [today's date]).

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