Is CHRNA2 p.Val387Met (c.1159G>A) pathogenic?

CHRNA2 p.Val387Met (c.1159G>A) is classified Likely benign in CHRNA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-29). AlphaMissense: likely benign (0.0749); Ultra-rare (popmax 0.0275%, sas); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNA2 p.Val387Met (c.1159G>A)?

CHRNA2 p.Val387Met (c.1159G>A) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNA2 p.Val387Met (c.1159G>A) in the general population?

CHRNA2 p.Val387Met (c.1159G>A) is ultra-rare (popmax 0.0275%, 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.Val387Met (c.1159G>A)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

CHRNA2 p.Val387Met

c.1159G>A · rs749494357 · VCV844760

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0275%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -7.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -3.5
Regional constraint	o/e 1.05	unconstrained · MANE · 1,855 bp · p 0.38 · regional, not allelic
Overall
CADD	2.815	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 0.0275% South Asian · 25/90,816 alleles

Filtering AF 0.019% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0163%

Overall 0.00187% 30/1,608,366 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0275%	3,633
East Asian	0.00223%	44,780
African / African-American	0.00134%	74,860
European (non-Finnish)	0.000255%	391,974

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.Val387Met
Coding: c.1159G>A
MANE Select: NM_000742
dbSNP: rs749494357
Type: single nucleotide variant
Location: chr8:27463284 (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.Val387Ala Uncertain significance ★ ⚠ same residue
CHRNA2 p.Val387= 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
CHRNA2 c.449+3A>T Uncertain significance ★★ same condition
CHRNA2 c.73+4A>C 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-val387met (accessed [today's date]).

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