Is CHRNB2 p.Val287Met (c.859G>A) pathogenic?

CHRNB2 p.Val287Met (c.859G>A) is classified Pathogenic in CHRNB2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-02-16). AlphaMissense: likely pathogenic (0.875); Absent from gnomAD v4.1; Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNB2 p.Val287Met (c.859G>A)?

CHRNB2 p.Val287Met (c.859G>A) is associated with familial sleep-related hypermotor epilepsy, autosomal dominant nocturnal frontal lobe epilepsy 1, autosomal dominant nocturnal frontal lobe epilepsy 3 (ClinVar).

How common is CHRNB2 p.Val287Met (c.859G>A) in the general population?

CHRNB2 p.Val287Met (c.859G>A) is absent from gnomAD v4.1 (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.Val287Met (c.859G>A)?

AlphaMissense predicts likely pathogenic (score 0.875) — an in-silico prediction, not a clinical call.

CHRNB2 p.Val287Met

c.859G>A · rs74315291 · VCV17496

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.875 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
AlphaMissense	0.875	likely pathogenic ✓ concordant with ClinVar
REVEL	0.735	pathogenic-leaning
SaProt	LLR -9.34	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 0.95, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,773 bp · p 1.9e-08 · regional, not allelic
Overall
CADD	29.8	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

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: CHRNB2
Protein: p.Val287Met
Coding: c.859G>A
MANE Select: NM_000748
dbSNP: rs74315291
Type: single nucleotide variant
Location: chr1:154571682 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 15 PDB
Residue 287: a UniProt-annotated variant site (in enfl3); a UniProt-annotated variant site (in enfl3; approximately 10-fold increase in acetylcholine sensitivity)

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 1 autosomal dominant nocturnal frontal lobe epilepsy 3

For Sleep-related hypermotor epilepsy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

CHRNB2 p.Val287Leu Pathogenic/Likely pathogenic ★★ same residue
CHRNB2 p.Val287= Likely benign ★ same residue
CHRNB2 p.Val287_Pro289del Uncertain significance ★★ same residue
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
CHRNB2 p.Ala154Thr 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-val287met (accessed [today's date]).

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