Is CHRNB2 p.Ser21= (c.63A>G) pathogenic?

CHRNB2 p.Ser21= (c.63A>G) is classified Uncertain significance in CHRNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-29). Very rare (popmax 0.00134%, afr); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNB2 p.Ser21= (c.63A>G)?

CHRNB2 p.Ser21= (c.63A>G) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNB2 p.Ser21= (c.63A>G) in the general population?

CHRNB2 p.Ser21= (c.63A>G) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Sleep-related hypermotor epilepsy inherited?

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

CHRNB2 p.Ser21=

c.63A>G · rs2526359637 · VCV2033339

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.8	GERP 1.4, phastCons 1
Overall
CADD	17.83	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,862 alleles

Overall 0.000125% 2/1,601,738 alleles · very rare exomes 2/1,449,398 · genomes 0/152,340 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,862
South Asian	0.00113%	88,762

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.Ser21=
Coding: c.63A>G
MANE Select: NM_000748
dbSNP: rs2526359637
Type: single nucleotide variant
Location: chr1:154568107 (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.Ser21Pro 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
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-ser21 (accessed [today's date]).

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