Is CHRNA2 p.Arg121Ser (c.361C>A) pathogenic?

CHRNA2 p.Arg121Ser (c.361C>A) is classified Uncertain significance in CHRNA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-12). AlphaMissense: likely benign (0.324); Absent from gnomAD v4.1; Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNA2 p.Arg121Ser (c.361C>A)?

CHRNA2 p.Arg121Ser (c.361C>A) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNA2 p.Arg121Ser (c.361C>A) in the general population?

CHRNA2 p.Arg121Ser (c.361C>A) is absent from gnomAD v4.1 (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.Arg121Ser (c.361C>A)?

AlphaMissense predicts likely benign (score 0.324) — an in-silico prediction, not a clinical call.

CHRNA2 p.Arg121Ser

c.361C>A · rs746274421 · VCV421927

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.324 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,602)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
AlphaMissense	0.324	likely benign
REVEL	0.502	indeterminate
SaProt	LLR -9.66	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 5	GERP -0.39, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 7,404 bp · p 0.095 · regional, not allelic
Overall
CADD	23.5	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

No allele count reported in gnomAD v4.1 (AN 1,613,602). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CHRNA2
Protein: p.Arg121Ser
Coding: c.361C>A
MANE Select: NM_000742
dbSNP: rs746274421
Type: single nucleotide variant
Location: chr8:27467317 (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 p.Arg121Cys Uncertain significance ★★ ⚠ same residue
CHRNA2 p.Arg121Leu Uncertain significance ★★ ⚠ same residue
CHRNA2 p.Arg121His Conflicting classifications of pathogenicity ★ ⚠ same residue
CHRNA2 p.Arg121= Likely benign ★ 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

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-arg121ser (accessed [today's date]).

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