Is CHRNA4 p.Pro554= (c.1662G>A) pathogenic?

CHRNA4 p.Pro554= (c.1662G>A) is classified Benign/Likely benign in CHRNA4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Rare (popmax 0.525%, afr); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNA4 p.Pro554= (c.1662G>A)?

CHRNA4 p.Pro554= (c.1662G>A) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNA4 p.Pro554= (c.1662G>A) in the general population?

CHRNA4 p.Pro554= (c.1662G>A) is rare (popmax 0.525%, afr) (gnomAD).

How is Sleep-related hypermotor epilepsy inherited?

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

CHRNA4 p.Pro554=

c.1662G>A · rs121912284 · VCV98322

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.525%, afr)

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 -20	GERP -8.3
Overall
CADD	0.024	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.525% African / African-American · 394/75,032 alleles

Filtering AF 0.482% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.466%

Overall 0.028% 452/1,612,186 alleles · rare exomes 217/1,459,884 · genomes 235/152,302 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.525%	190
Remaining individualsnot grpmax-eligible	0.0416%	2,402
Middle Eastern	0.033%	3,030
Admixed American	0.03%	3,332
South Asian	0.0011%	91,026
European (non-Finnish)	0.000933%	107,225

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.Pro554=
Coding: c.1662G>A
MANE Select: NM_000744
dbSNP: rs121912284
Type: single nucleotide variant
Location: chr20:63349749 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.42 · 12 PDB
Residue 554: 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.Pro554Leu Likely benign ★ 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-pro554 (accessed [today's date]).

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