Is CHRNB2 p.Ala135Val (c.404C>T) pathogenic?

CHRNB2 p.Ala135Val (c.404C>T) is classified Uncertain significance in CHRNB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-11). AlphaMissense: likely benign (0.2797); Very rare (popmax 0.00133%, afr); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNB2 p.Ala135Val (c.404C>T)?

CHRNB2 p.Ala135Val (c.404C>T) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNB2 p.Ala135Val (c.404C>T) in the general population?

CHRNB2 p.Ala135Val (c.404C>T) is very rare (popmax 0.00133%, afr) (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.Ala135Val (c.404C>T)?

AlphaMissense predicts likely benign (score 0.2797) — an in-silico prediction, not a clinical call.

CHRNB2 p.Ala135Val

c.404C>T · rs1060502835 · VCV410309

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2797 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
AlphaMissense	0.2797	likely benign
REVEL	0.436	indeterminate
SaProt	LLR -6.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -1.3, phastCons 0.99
Regional constraint	o/e 0.74	unconstrained · MANE · 3,773 bp · p 1.9e-08 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,038 alleles

Overall 0.000137% 2/1,461,860 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,038
European (non-Finnish)	8.47e-05%	1,180,040

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.Ala135Val
Coding: c.404C>T
MANE Select: NM_000748
dbSNP: rs1060502835
Type: single nucleotide variant
Location: chr1:154571227 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 15 PDB
Residue 135: a β-strand

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.Ala135= Likely benign ★ 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.Ala154Thr Uncertain significance ★★ ⚠ same condition
CHRNB2 p.Ala207Gly 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-ala135val (accessed [today's date]).

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