Is CHRNB2 p.Ser446= (c.1338C>T) pathogenic?

CHRNB2 p.Ser446= (c.1338C>T) is classified Uncertain significance in CHRNB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-16). Very rare (popmax 0.00196%, amr); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNB2 p.Ser446= (c.1338C>T)?

CHRNB2 p.Ser446= (c.1338C>T) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNB2 p.Ser446= (c.1338C>T) in the general population?

CHRNB2 p.Ser446= (c.1338C>T) is very rare (popmax 0.00196%, amr) (gnomAD).

How is Sleep-related hypermotor epilepsy inherited?

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

CHRNB2 p.Ser446=

c.1338C>T · rs201462348 · VCV1511375

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00196%, amr)

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.22	donor gain · deltas
Constraint at this position
Conservation	phyloP -2	GERP -3.6
Overall
CADD	12.09	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00196% Admixed American · 1/50,946 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000361% 5/1,384,702 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00196%	50,946
African / African-American	0.00137%	73,054
South Asian	0.00119%	83,976
European (non-Finnish)	0.000174%	573,250

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.Ser446=
Coding: c.1338C>T
MANE Select: NM_000748
dbSNP: rs201462348
Type: single nucleotide variant
Location: chr1:154572161 (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.Ser446Gly 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-ser446 (accessed [today's date]).

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