Is CHRNB2 p.Gln397His (c.1191G>C) pathogenic?

CHRNB2 p.Gln397His (c.1191G>C) is classified Conflicting classifications of pathogenicity in CHRNB2 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1243); Low-frequency (popmax 1.42%, nfe); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNB2 p.Gln397His (c.1191G>C)?

CHRNB2 p.Gln397His (c.1191G>C) is associated with familial sleep-related hypermotor epilepsy, autosomal dominant nocturnal frontal lobe epilepsy 3 (ClinVar).

How common is CHRNB2 p.Gln397His (c.1191G>C) in the general population?

CHRNB2 p.Gln397His (c.1191G>C) is low-frequency (popmax 1.42%, nfe) (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.Gln397His (c.1191G>C)?

AlphaMissense predicts likely benign (score 0.1243) — an in-silico prediction, not a clinical call.

CHRNB2 p.Gln397His

c.1191G>C · rs55685423 · VCV158330

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.1243 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.42%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
AlphaMissense	0.1243	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -6.00	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 0.57	GERP -0.78, phastCons 0.39
Regional constraint	o/e 1.09	unconstrained · MANE · 4,110 bp · p 0.17 · regional, not allelic
Overall
CADD	14.37	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 1.42% European (non-Finnish) · 16,272/1,144,954 alleles

Filtering AF 1.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4%

Overall 1.15% 17,612/1,533,948 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.42%	70
Remaining individualsnot grpmax-eligible	1%	100
Amishnot grpmax-eligible	0.768%	130
Admixed American	0.419%	239
South Asian	0.26%	385
African / African-American	0.248%	404
Finnishnot grpmax-eligible	0.233%	429
Middle Eastern	0.0532%	1,881
Ashkenazi Jewishnot grpmax-eligible	0.0456%	2,194

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.Gln397His
Coding: c.1191G>C
MANE Select: NM_000748
dbSNP: rs55685423
Type: single nucleotide variant
Location: chr1:154572014 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 15 PDB
Residue 397: a UniProt-annotated variant site (in)

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

Also linked: autosomal dominant nocturnal frontal lobe epilepsy 3

For Sleep-related hypermotor epilepsy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

CHRNB2 p.Gln397Arg Uncertain significance ★ ⚠ same residue
CHRNB2 p.Gln397Pro 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-gln397his (accessed [today's date]).

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