Is CHRNB2 p.Thr220Pro (c.658A>C) pathogenic?

CHRNB2 p.Thr220Pro (c.658A>C) is classified Uncertain significance in CHRNB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-06). AlphaMissense: ambiguous (0.3635); Very rare (popmax 0.00347%, nfe); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNB2 p.Thr220Pro (c.658A>C)?

CHRNB2 p.Thr220Pro (c.658A>C) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNB2 p.Thr220Pro (c.658A>C) in the general population?

CHRNB2 p.Thr220Pro (c.658A>C) is very rare (popmax 0.00347%, 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.Thr220Pro (c.658A>C)?

AlphaMissense predicts ambiguous (score 0.3635) — an in-silico prediction, not a clinical call.

CHRNB2 p.Thr220Pro

c.658A>C · rs374183227 · VCV1425157

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3635 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00347%, nfe)

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
AlphaMissense	0.3635	ambiguous
REVEL	0.576	indeterminate
SaProt	LLR -15.05	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 0.97, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,773 bp · p 1.9e-08 · regional, not allelic
Overall
CADD	23.8	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

Grpmax group 0.00347% European (non-Finnish) · 41/1,180,006 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00285% 46/1,613,882 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)grpmax	0.00347%	28,781

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr220Pro
Coding: c.658A>C
MANE Select: NM_000748
dbSNP: rs374183227
Type: single nucleotide variant
Location: chr1:154571481 (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.Thr220Met Uncertain significance ★★ ⚠ same residue
CHRNB2 p.Thr220= Likely benign ★ same residue
CHRNB2 p.Thr220Ala 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

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-thr220pro (accessed [today's date]).

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