Is CHRNA3 p.Arg477Ser (c.1429C>A) pathogenic?

CHRNA3 p.Arg477Ser (c.1429C>A) is classified Uncertain significance in CHRNA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-02). AlphaMissense: likely pathogenic (0.9939); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CHRNA3 p.Arg477Ser (c.1429C>A)?

CHRNA3 p.Arg477Ser (c.1429C>A) is associated with Inborn genetic diseases (ClinVar).

How common is CHRNA3 p.Arg477Ser (c.1429C>A) in the general population?

CHRNA3 p.Arg477Ser (c.1429C>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CHRNA3 p.Arg477Ser (c.1429C>A)?

AlphaMissense predicts likely pathogenic (score 0.9939) — an in-silico prediction, not a clinical call.

CHRNA3 p.Arg477Ser

c.1429C>A · rs751042207 · VCV2304521

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9939 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9939	likely pathogenic · top 5% in CHRNA3
REVEL	0.875	moderately pathogenic-leaning
SaProt	LLR -14.50	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.29	loss · gain 0.02 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 8.6	GERP -1.4, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 24 kb · p 0.00014 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,734 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,460,464 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	63,926
European (non-Finnish)grpmax	0.000254%	393,244

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg477Ser
Coding: c.1429C>A
MANE Select: NM_000743
dbSNP: rs751042207
Type: single nucleotide variant
Location: chr15:78596693 (GRCh38)
Gene constraint: LOEUF 1.065 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.97 · 5 PDB
Residue 477: 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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHRNA3 p.Arg477His Uncertain significance ★★ ⚠ same residue
CHRNA3 p.Leu380Val Uncertain significance ★★ ⚠ same condition
CHRNA3 p.Pro498Leu Uncertain significance ★★ ⚠ same condition
CHRNA3 p.Ala127Val Uncertain significance ★ ⚠ same condition
CHRNA3 p.Ala366Val Uncertain significance ★ ⚠ same condition
CHRNA3 p.Arg16Trp Uncertain significance ★ ⚠ same condition
CHRNA3 p.Arg238Trp Uncertain significance ★ ⚠ same condition
CHRNA3 p.Arg408His 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/chrna3-p-arg477ser (accessed [today's date]).

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