Is CHRNA2 p.Arg61Pro (c.182G>C) pathogenic?

CHRNA2 p.Arg61Pro (c.182G>C) is classified Likely benign in CHRNA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-15). AlphaMissense: likely pathogenic (0.6046); Very rare (popmax 0.0011%, sas); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNA2 p.Arg61Pro (c.182G>C)?

CHRNA2 p.Arg61Pro (c.182G>C) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNA2 p.Arg61Pro (c.182G>C) in the general population?

CHRNA2 p.Arg61Pro (c.182G>C) is very rare (popmax 0.0011%, sas) (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.Arg61Pro (c.182G>C)?

AlphaMissense predicts likely pathogenic (score 0.6046) — an in-silico prediction, not a clinical call.

CHRNA2 p.Arg61Pro

c.182G>C · rs568479156 · VCV2080496

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6046 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
AlphaMissense	0.6046	likely pathogenic
REVEL	0.535	indeterminate
SaProt	LLR -18.20	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.86	GERP 1.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 7,404 bp · p 0.095 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,074 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000821% 12/1,461,870 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,512
South Asiangrpmax	0.0011%	91,074
European (non-Finnish)	0.000847%	118,003

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg61Pro
Coding: c.182G>C
MANE Select: NM_000742
dbSNP: rs568479156
Type: single nucleotide variant
Location: chr8:27469873 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 1 PDB
Residue 61: an α-helix

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.Arg61= Likely benign ★★ same residue
CHRNA2 p.Arg61Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CHRNA2 p.Arg61Trp 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-arg61pro (accessed [today's date]).

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