Is CHRNA3 p.Pro339Leu (c.1016C>T) pathogenic?

CHRNA3 p.Pro339Leu (c.1016C>T) is classified Uncertain significance in CHRNA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely pathogenic (0.8872); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CHRNA3 p.Pro339Leu (c.1016C>T)?

CHRNA3 p.Pro339Leu (c.1016C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHRNA3 p.Pro339Leu (c.1016C>T) in the general population?

CHRNA3 p.Pro339Leu (c.1016C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHRNA3 p.Pro339Leu (c.1016C>T)?

AlphaMissense predicts likely pathogenic (score 0.8872) — an in-silico prediction, not a clinical call.

CHRNA3 p.Pro339Leu

c.1016C>T · VCV4002618

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8872 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8872	likely pathogenic
REVEL	0.706	pathogenic-leaning
SaProt	LLR -12.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 24 kb · p 0.00014 · regional, not allelic
Overall
CADD	24.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHRNA3
Protein: p.Pro339Leu
Coding: c.1016C>T
MANE Select: NM_000743
Type: single nucleotide variant
Location: chr15:78601626 (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

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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-pro339leu (accessed [today's date]).

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