Is CHRNA2 p.Ser488= (c.1464G>A) pathogenic?

CHRNA2 p.Ser488= (c.1464G>A) is classified Conflicting classifications of pathogenicity in CHRNA2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-01-06). Very rare (popmax 0.00934%, afr); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNA2 p.Ser488= (c.1464G>A)?

CHRNA2 p.Ser488= (c.1464G>A) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNA2 p.Ser488= (c.1464G>A) in the general population?

CHRNA2 p.Ser488= (c.1464G>A) is very rare (popmax 0.00934%, afr) (gnomAD).

How is Sleep-related hypermotor epilepsy inherited?

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

CHRNA2 p.Ser488=

c.1464G>A · rs796052305 · VCV204975

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.69	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.46	loss · gain 0.05 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.23	GERP -2.7, phastCons 0.98
Overall
CADD	15.37	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00934% African / African-American · 7/74,950 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00173% 28/1,613,916 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,707
Remaining individualsnot grpmax-eligible	0.0048%	20,827
Admixed American	0.00333%	30,008
European (non-Finnish)	0.00127%	78,668
South Asian	0.0011%	91,082

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.Ser488=
Coding: c.1464G>A
MANE Select: NM_000742
dbSNP: rs796052305
Type: single nucleotide variant
Location: chr8:27462979 (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.Ser488Leu 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
CHRNA2 c.73+4A>C Uncertain significance ★★ same condition
CHRNA2 p.Ala177Pro 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-ser488 (accessed [today's date]).

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