Is CHRNA4 p.Pro559= (c.1677C>T) pathogenic?

CHRNA4 p.Pro559= (c.1677C>T) is classified Likely benign in CHRNA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-14). Very rare (popmax 0.00167%, amr); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNA4 p.Pro559= (c.1677C>T)?

CHRNA4 p.Pro559= (c.1677C>T) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNA4 p.Pro559= (c.1677C>T) in the general population?

CHRNA4 p.Pro559= (c.1677C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Sleep-related hypermotor epilepsy inherited?

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

CHRNA4 p.Pro559=

c.1677C>T · rs767662388 · VCV669373

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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 -0.5	GERP -0.98
Overall
CADD	2.71	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,992 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.00062% 10/1,612,616 alleles · very rare exomes 8/1,460,358 · genomes 2/152,258 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,992
South Asian	0.0011%	91,066
European (non-Finnish)	0.000678%	147,482

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.Pro559=
Coding: c.1677C>T
MANE Select: NM_000744
dbSNP: rs767662388
Type: single nucleotide variant
Location: chr20:63349734 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.42 · 12 PDB
Residue 559: the 'disordered' region

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.Pro559Leu 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
CHRNA4 c.383+1G>A Uncertain significance ★★ same condition
CHRNA4 p.Ala134Thr Uncertain significance ★★ ⚠ same condition
CHRNA4 p.Ala26Val 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-pro559 (accessed [today's date]).

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