Is SCN2B p.His2Pro (c.5A>C) pathogenic?

SCN2B p.His2Pro (c.5A>C) is classified Uncertain significance in SCN2B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-02). AlphaMissense: likely benign (0.0466); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with SCN2B p.His2Pro (c.5A>C)?

SCN2B p.His2Pro (c.5A>C) is associated with Cardiovascular phenotype (ClinVar).

How common is SCN2B p.His2Pro (c.5A>C) in the general population?

SCN2B p.His2Pro (c.5A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SCN2B p.His2Pro (c.5A>C)?

AlphaMissense predicts likely benign (score 0.0466) — an in-silico prediction, not a clinical call.

SCN2B p.His2Pro

c.5A>C · rs765743471 · VCV1750974

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0466 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0466	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -4.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.85	GERP 0.024, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 9,541 bp · p 0.14 · regional, not allelic
Overall
CADD	16.89	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SCN2B
Protein: p.His2Pro
Coding: c.5A>C
MANE Select: NM_004588
dbSNP: rs765743471
Type: single nucleotide variant
Location: chr11:118176427 (GRCh38)
Gene constraint: LOEUF 1.15 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.03 · 35 PDB

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

Similar variants

SCN2B p.His2Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
SCN2B p.Ala171Pro Uncertain significance ★★ ⚠ same condition
SCN2B p.Arg137His Uncertain significance ★★ ⚠ same condition
SCN2B p.Arg185Thr Uncertain significance ★★ ⚠ same condition
SCN2B p.Arg84Cys Uncertain significance ★★ ⚠ same condition
SCN2B p.Arg98Gly Uncertain significance ★★ ⚠ same condition
SCN2B p.Asp109Asn Uncertain significance ★★ same condition
SCN2B p.Asp211Gly 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-his2pro (accessed [today's date]).

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