Is CHRNB2 p.Arg366Cys (c.1096C>T) pathogenic?

CHRNB2 p.Arg366Cys (c.1096C>T) is classified Uncertain significance in CHRNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). AlphaMissense: likely benign (0.1537); Very rare (popmax 0.00229%, sas); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNB2 p.Arg366Cys (c.1096C>T)?

CHRNB2 p.Arg366Cys (c.1096C>T) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNB2 p.Arg366Cys (c.1096C>T) in the general population?

CHRNB2 p.Arg366Cys (c.1096C>T) is very rare (popmax 0.00229%, sas) (gnomAD).

How is Sleep-related hypermotor epilepsy inherited?

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

What do computational predictors say about CHRNB2 p.Arg366Cys (c.1096C>T)?

AlphaMissense predicts likely benign (score 0.1537) — an in-silico prediction, not a clinical call.

CHRNB2 p.Arg366Cys

c.1096C>T · rs2526371911 · VCV2851731

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1537 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
AlphaMissense	0.1537	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -9.81	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 4.7	GERP 1.7, phastCons 0.98
Regional constraint	o/e 1.09	unconstrained · MANE · 4,110 bp · p 0.17 · regional, not allelic
Overall
CADD	22.7	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 0.00229% South Asian · 2/87,178 alleles

Filtering AF 0.000381% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000143%

Overall 0.000191% 3/1,568,194 alleles · very rare exomes 3/1,415,804 · genomes 0/152,390 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00229%	43,589
European (non-Finnish)	8.61e-05%	1,161,730

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: CHRNB2
Protein: p.Arg366Cys
Coding: c.1096C>T
MANE Select: NM_000748
dbSNP: rs2526371911
Type: single nucleotide variant
Location: chr1:154571919 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 15 PDB

Full CHRNB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial sleep-related hypermotor epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sleep-related hypermotor epilepsy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

CHRNB2 p.Arg366= Likely benign ★ same residue
CHRNB2 p.Arg366_Gln367insArg Uncertain significance ★ same residue
CHRNB2 p.Val287Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
CHRNB2 p.Val287Met Pathogenic ★★ ⚠ same condition
CHRNB2 p.Val308Ala Pathogenic/Likely pathogenic ★★ same condition
CHRNB2 c.1338+3G>T Uncertain significance ★★ same condition
CHRNB2 c.366-3C>T Uncertain significance ★★ same condition
CHRNB2 p.Ala135Val 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/chrnb2-p-arg366cys (accessed [today's date]).

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