Is CHRNA2 p.Ser291= (c.873C>T) pathogenic?

CHRNA2 p.Ser291= (c.873C>T) is classified Conflicting classifications of pathogenicity in CHRNA2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-11-19). Very rare (popmax 0.00619%, nfe); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNA2 p.Ser291= (c.873C>T)?

CHRNA2 p.Ser291= (c.873C>T) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNA2 p.Ser291= (c.873C>T) in the general population?

CHRNA2 p.Ser291= (c.873C>T) is very rare (popmax 0.00619%, nfe) (gnomAD).

How is Sleep-related hypermotor epilepsy inherited?

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

CHRNA2 p.Ser291=

c.873C>T · rs76140563 · VCV166881

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00619%, nfe)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.3	GERP -4.2
Overall
CADD	5.854	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00619% European (non-Finnish) · 73/1,180,042 alleles

Filtering AF 0.00503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00462%

Overall 0.00489% 79/1,614,098 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00619%	16,165
Admixed American	0.005%	20,003
Remaining individualsnot grpmax-eligible	0.0032%	31,245
African / African-American	0.00133%	74,932

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.Ser291=
Coding: c.873C>T
MANE Select: NM_000742
dbSNP: rs76140563
Type: single nucleotide variant
Location: chr8:27463570 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 1 PDB

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 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
CHRNA2 c.73+4A>C Uncertain significance ★★ same condition
CHRNA2 p.Ala177Pro Uncertain significance ★★ ⚠ same condition
CHRNA2 p.Ala36Ser 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-ser291 (accessed [today's date]).

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