Is CHRNA2 p.Arg68Pro (c.203G>C) pathogenic?

CHRNA2 p.Arg68Pro (c.203G>C) is classified Conflicting classifications of pathogenicity in CHRNA2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-07-19). AlphaMissense: likely benign (0.2816); Very rare (popmax 0.00133%, afr); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNA2 p.Arg68Pro (c.203G>C)?

CHRNA2 p.Arg68Pro (c.203G>C) is associated with familial sleep-related hypermotor epilepsy, autosomal dominant nocturnal frontal lobe epilepsy 4 (ClinVar).

How common is CHRNA2 p.Arg68Pro (c.203G>C) in the general population?

CHRNA2 p.Arg68Pro (c.203G>C) 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.Arg68Pro (c.203G>C)?

AlphaMissense predicts likely benign (score 0.2816) — an in-silico prediction, not a clinical call.

CHRNA2 p.Arg68Pro

c.203G>C · rs548268816 · VCV362698

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2816 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
AlphaMissense	0.2816	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -13.24	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.83 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.49	GERP 1.1
Regional constraint	o/e 0.91	unconstrained · MANE · 7,404 bp · p 0.095 · regional, not allelic
Overall
CADD	18.37	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 0.00133% African / African-American · 1/74,914 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,970 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,914
European (non-Finnish)	0.000169%	590,016

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.Arg68Pro
Coding: c.203G>C
MANE Select: NM_000742
dbSNP: rs548268816
Type: single nucleotide variant
Location: chr8:27469852 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 1 PDB
Residue 68: 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

Also linked: autosomal dominant nocturnal frontal lobe epilepsy 4

For Sleep-related hypermotor epilepsy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

CHRNA2 p.Arg68Gln Likely benign ★★ same residue
CHRNA2 p.Arg68Leu Uncertain significance ★ ⚠ same residue
CHRNA2 p.Arg68Trp Conflicting classifications of pathogenicity ★ ⚠ 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-arg68pro (accessed [today's date]).

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