Is CHRNA2 p.Ser228= (c.684C>T) pathogenic?

CHRNA2 p.Ser228= (c.684C>T) is classified Benign/Likely benign in CHRNA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-19). Rare (popmax 0.235%, afr); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNA2 p.Ser228= (c.684C>T)?

CHRNA2 p.Ser228= (c.684C>T) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNA2 p.Ser228= (c.684C>T) in the general population?

CHRNA2 p.Ser228= (c.684C>T) is rare (popmax 0.235%, afr) (gnomAD).

How is Sleep-related hypermotor epilepsy inherited?

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

CHRNA2 p.Ser228=

c.684C>T · rs143536618 · VCV377665

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.235%, afr)

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 -4.7	GERP -4.2
Overall
CADD	1.379	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.235% African / African-American · 176/75,034 alleles

Filtering AF 0.206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.195%

Overall 0.015% 242/1,614,130 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.235%	426
South Asian	0.034%	2,938
Remaining individualsnot grpmax-eligible	0.0192%	5,209
Middle Eastern	0.0165%	6,062
Admixed American	0.01%	10,002
European (non-Finnish)	0.00136%	73,751

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.Ser228=
Coding: c.684C>T
MANE Select: NM_000742
dbSNP: rs143536618
Type: single nucleotide variant
Location: chr8:27463759 (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-ser228 (accessed [today's date]).

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