Is CHRNA3 p.Arg16Trp (c.46C>T) pathogenic?

CHRNA3 p.Arg16Trp (c.46C>T) is classified Uncertain significance in CHRNA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-10). AlphaMissense: likely benign (0.2424); Very rare (popmax 0.000177%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CHRNA3 p.Arg16Trp (c.46C>T)?

CHRNA3 p.Arg16Trp (c.46C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHRNA3 p.Arg16Trp (c.46C>T) in the general population?

CHRNA3 p.Arg16Trp (c.46C>T) is very rare (popmax 0.000177%, nfe) (gnomAD).

What do computational predictors say about CHRNA3 p.Arg16Trp (c.46C>T)?

AlphaMissense predicts likely benign (score 0.2424) — an in-silico prediction, not a clinical call.

CHRNA3 p.Arg16Trp

c.46C>T · VCV3492536

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2424 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000177%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2424	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -7.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.033	GERP -1.5
Regional constraint	o/e 0.85	unconstrained · MANE · 24 kb · p 0.00014 · regional, not allelic
Overall
CADD	17.76	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000177% European (non-Finnish) · 2/1,130,890 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000149% 2/1,346,640 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.Arg16Trp
Coding: c.46C>T
MANE Select: NM_000743
Type: single nucleotide variant
Location: chr15:78620749 (GRCh38)
Gene constraint: LOEUF 1.065 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.97 · 5 PDB

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 condition
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.Arg238Trp Uncertain significance ★ ⚠ same condition
CHRNA3 p.Arg408His Uncertain significance ★ same condition
CHRNA3 p.Arg41Trp 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-arg16trp (accessed [today's date]).

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