Is CHRNB2 p.Arg91Cys (c.271C>T) pathogenic?

CHRNB2 p.Arg91Cys (c.271C>T) is classified Uncertain significance in CHRNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-02). AlphaMissense: likely pathogenic (0.9799); Ultra-rare (popmax 0.0166%, mid); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNB2 p.Arg91Cys (c.271C>T)?

CHRNB2 p.Arg91Cys (c.271C>T) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNB2 p.Arg91Cys (c.271C>T) in the general population?

CHRNB2 p.Arg91Cys (c.271C>T) is ultra-rare (popmax 0.0166%, mid) (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.Arg91Cys (c.271C>T)?

AlphaMissense predicts likely pathogenic (score 0.9799) — an in-silico prediction, not a clinical call.

CHRNB2 p.Arg91Cys

c.271C>T · rs754725293 · VCV1352304

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9799 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
AlphaMissense	0.9799	likely pathogenic
REVEL	0.77	pathogenic-leaning
SaProt	LLR -12.85	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,773 bp · p 1.9e-08 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0166% Middle Eastern · 1/6,036 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000745% 12/1,610,184 alleles · ultra-rare exomes 10/1,458,122 · genomes 2/152,062 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,036
African / African-American	0.00267%	37,423
South Asian	0.00221%	45,174
European (non-Finnish)	0.000594%	168,261

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.Arg91Cys
Coding: c.271C>T
MANE Select: NM_000748
dbSNP: rs754725293
Type: single nucleotide variant
Location: chr1:154570273 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 15 PDB
Residue 91: 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.Arg91His Likely benign ★★ ⚠ same residue
CHRNB2 p.Arg91Gly 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-arg91cys (accessed [today's date]).

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