Is CHRNA3 p.Cys487Ser (c.1459T>A) pathogenic?

CHRNA3 p.Cys487Ser (c.1459T>A) is classified Uncertain significance in CHRNA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-03). AlphaMissense: likely pathogenic (0.6347); Very rare (popmax 0.00503%, amr).

How common is CHRNA3 p.Cys487Ser (c.1459T>A) in the general population?

CHRNA3 p.Cys487Ser (c.1459T>A) is very rare (popmax 0.00503%, amr) (gnomAD).

What do computational predictors say about CHRNA3 p.Cys487Ser (c.1459T>A)?

AlphaMissense predicts likely pathogenic (score 0.6347) — an in-silico prediction, not a clinical call.

CHRNA3 p.Cys487Ser

c.1459T>A · rs772596477 · VCV2133189

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6347 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00503%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6347	likely pathogenic
REVEL	0.868	moderately pathogenic-leaning
SaProt	LLR -9.82	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.20	acceptor loss, 10 bp away · masked 0 · deltas
Pangolin	Δ0.51	gain · loss 0.00 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 24 kb · p 0.00014 · regional, not allelic
Overall
CADD	25.4	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 0.00503% Admixed American · 3/59,614 alleles

Filtering AF 0.00134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00067%

Overall 0.000205% 3/1,461,036 alleles · very rare

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: CHRNA3
Protein: p.Cys487Ser
Coding: c.1459T>A
MANE Select: NM_000743
dbSNP: rs772596477
Type: single nucleotide variant
Location: chr15:78596663 (GRCh38)
Gene constraint: LOEUF 1.065 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.97 · 5 PDB
Residue 487: a UniProt-annotated variant site (in baiprck; loss-of-function variant affecting ion transmembrane transport in response to acetylcholine; does not localize to plasma membrane); an α-helix

Full CHRNA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHRNA3 p.Trp180Ter Likely pathogenic ★★ same type
CHRNA3 p.Arg477His Uncertain significance ★★ ⚠ same type
CHRNA3 p.Asn92Ser Uncertain significance ★★ ⚠ same type
CHRNA3 p.Asp230Asn Uncertain significance ★★ ⚠ same type
CHRNA3 p.Gly390Ala Uncertain significance ★★ ⚠ same type
CHRNA3 p.Gly493Ala Uncertain significance ★★ ⚠ same type
CHRNA3 p.Leu380Val Uncertain significance ★★ ⚠ same type
CHRNA3 p.Pro498Leu Uncertain significance ★★ ⚠ same type

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/chrna3-p-cys487ser (accessed [today's date]).

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