Is CHRNB2 p.Arg460Cys (c.1378C>T) pathogenic?

CHRNB2 p.Arg460Cys (c.1378C>T) is classified Conflicting classifications of pathogenicity in CHRNB2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-07-20). AlphaMissense: likely pathogenic (0.9365); Very rare (popmax 0.0022%, sas); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNB2 p.Arg460Cys (c.1378C>T)?

CHRNB2 p.Arg460Cys (c.1378C>T) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNB2 p.Arg460Cys (c.1378C>T) in the general population?

CHRNB2 p.Arg460Cys (c.1378C>T) is very rare (popmax 0.0022%, 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.Arg460Cys (c.1378C>T)?

AlphaMissense predicts likely pathogenic (score 0.9365) — an in-silico prediction, not a clinical call.

CHRNB2 p.Arg460Cys

c.1378C>T · rs202079239 · VCV1356911

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9365 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
AlphaMissense	0.9365	likely pathogenic
REVEL	0.881	moderately pathogenic-leaning
SaProt	LLR -12.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 4,110 bp · p 0.17 · regional, not allelic
Overall
CADD	32.0	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 0.0022% South Asian · 2/91,080 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00155% 25/1,613,996 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0125%	8,002
South Asiangrpmax	0.0022%	45,540
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	0.00119%	84,288

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg460Cys
Coding: c.1378C>T
MANE Select: NM_000748
dbSNP: rs202079239
Type: single nucleotide variant
Location: chr1:154575801 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 15 PDB
Residue 460: an α-helix

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.Arg460His Uncertain significance ★★ ⚠ same residue
CHRNB2 p.Arg460= Likely benign ★★ same residue
CHRNB2 p.Arg460Gly Benign/Likely benign ★★ 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

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-arg460cys (accessed [today's date]).

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