Is CHRNA2 p.Ile96Phe (c.286A>T) pathogenic?

CHRNA2 p.Ile96Phe (c.286A>T) is classified Uncertain significance in CHRNA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-20). AlphaMissense: likely pathogenic (0.9661); Very rare (popmax 0.00133%, afr); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNA2 p.Ile96Phe (c.286A>T)?

CHRNA2 p.Ile96Phe (c.286A>T) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNA2 p.Ile96Phe (c.286A>T) in the general population?

CHRNA2 p.Ile96Phe (c.286A>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 CHRNA2 p.Ile96Phe (c.286A>T)?

AlphaMissense predicts likely pathogenic (score 0.9661) — an in-silico prediction, not a clinical call.

CHRNA2 p.Ile96Phe

c.286A>T · rs149615415 · VCV204955

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9661 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
AlphaMissense	0.9661	likely pathogenic
REVEL	0.823	moderately pathogenic-leaning
SaProt	LLR -10.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 7,404 bp · p 0.095 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 · 1/75,026 alleles

Overall 0.000657% 1/152,272 alleles · very rare

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: CHRNA2
Protein: p.Ile96Phe
Coding: c.286A>T
MANE Select: NM_000742
dbSNP: rs149615415
Type: single nucleotide variant
Location: chr8:27469769 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 1 PDB
Residue 96: a β-strand

Full CHRNA2 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

CHRNA2 p.Ile96= Likely benign ★ same residue
CHRNA2 p.Ile96Met Likely benign ★ same residue
CHRNA2 p.Ile96Thr Uncertain significance same residue
CHRNA2 c.1464+4C>T Uncertain significance ★★ same condition
CHRNA2 c.1464+5G>A Uncertain significance ★★ same condition
CHRNA2 c.294+1G>A Uncertain significance ★★ same condition
CHRNA2 c.294+5G>A Uncertain significance ★★ same condition
CHRNA2 c.449+3A>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/chrna2-p-ile96phe (accessed [today's date]).

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