Is CHRNA4 p.Pro6= (c.18C>G) pathogenic?

CHRNA4 p.Pro6= (c.18C>G) is classified Likely benign in CHRNA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-24). Very rare (popmax 0.00287%, eas); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNA4 p.Pro6= (c.18C>G)?

CHRNA4 p.Pro6= (c.18C>G) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNA4 p.Pro6= (c.18C>G) in the general population?

CHRNA4 p.Pro6= (c.18C>G) is very rare (popmax 0.00287%, eas) (gnomAD).

How is Sleep-related hypermotor epilepsy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

CHRNA4 p.Pro6=

c.18C>G · rs887132573 · VCV2023428

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00287%, eas)

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.85	GERP -1.2
Overall
CADD	7.047	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00287% East Asian · 1/34,844 alleles

Overall 6.76e-05% 1/1,479,068 alleles · very rare exomes 1/1,327,224 · genomes 0/151,844 · joint denominator

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: CHRNA4
Protein: p.Pro6=
Coding: c.18C>G
MANE Select: NM_000744
dbSNP: rs887132573
Type: single nucleotide variant
Location: chr20:63361148 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.42 · 12 PDB

Full CHRNA4 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

CHRNA4 p.Pro6Ser Likely benign ★★ same residue
CHRNA4 p.Pro6Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CHRNA4 p.Pro6Leu Likely benign ★ same residue
CHRNA4 p.Pro6Ala Uncertain significance ★ ⚠ same residue
CHRNA4 p.Ile275Phe Likely pathogenic ★★ same condition
CHRNA4 p.Ser280Phe Pathogenic ★★ same condition
CHRNA4 p.Ser284Leu Pathogenic ★★ same condition
CHRNA4 c.274-1G>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/chrna4-p-pro6 (accessed [today's date]).

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