Is CHRNA2 p.Pro392Ser (c.1174C>T) pathogenic?

CHRNA2 p.Pro392Ser (c.1174C>T) is classified Likely benign in CHRNA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-30). AlphaMissense: likely benign (0.077); Ultra-rare (popmax 0.0243%, sas); Associated with Inborn genetic diseases.

What condition is associated with CHRNA2 p.Pro392Ser (c.1174C>T)?

CHRNA2 p.Pro392Ser (c.1174C>T) is associated with Inborn genetic diseases, familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNA2 p.Pro392Ser (c.1174C>T) in the general population?

CHRNA2 p.Pro392Ser (c.1174C>T) is ultra-rare (popmax 0.0243%, sas) (gnomAD).

What do computational predictors say about CHRNA2 p.Pro392Ser (c.1174C>T)?

AlphaMissense predicts likely benign (score 0.077) — an in-silico prediction, not a clinical call.

CHRNA2 p.Pro392Ser

c.1174C>T · rs762406891 · VCV384959

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.077 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0243%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.077	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -6.24	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 -0.44	GERP -3.8
Regional constraint	o/e 1.05	unconstrained · MANE · 1,855 bp · p 0.38 · regional, not allelic
Overall
CADD	0.169	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 0.0243% South Asian · 22/90,426 alleles

Filtering AF 0.0164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00218% 35/1,606,400 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0243%	4,110
Remaining individualsnot grpmax-eligible	0.00483%	20,705
European (non-Finnish)	0.000851%	117,473

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.Pro392Ser
Coding: c.1174C>T
MANE Select: NM_000742
dbSNP: rs762406891
Type: single nucleotide variant
Location: chr8:27463269 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial sleep-related hypermotor epilepsy

Similar variants

CHRNA2 p.Pro392= Likely benign ★★ same residue
CHRNA2 p.Pro392Ala Uncertain significance ★ ⚠ same residue
CHRNA2 p.Pro392Arg 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-pro392ser (accessed [today's date]).

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