Is CHRNA3 p.Ser67Phe (c.200C>T) pathogenic?

CHRNA3 p.Ser67Phe (c.200C>T) is classified Uncertain significance in CHRNA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-29). AlphaMissense: likely pathogenic (0.5659); Very rare (popmax 0.00167%, amr); Associated with SMOKING AS A QUANTITATIVE TRAIT LOCUS 3.

What condition is associated with CHRNA3 p.Ser67Phe (c.200C>T)?

CHRNA3 p.Ser67Phe (c.200C>T) is associated with SMOKING AS A QUANTITATIVE TRAIT LOCUS 3, urinary bladder, atony of (ClinVar).

How common is CHRNA3 p.Ser67Phe (c.200C>T) in the general population?

CHRNA3 p.Ser67Phe (c.200C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CHRNA3 p.Ser67Phe (c.200C>T)?

AlphaMissense predicts likely pathogenic (score 0.5659) — an in-silico prediction, not a clinical call.

CHRNA3 p.Ser67Phe

c.200C>T · VCV3577774

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5659 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SMOKING AS A QUANTITATIVE TRAIT LOCUS 3

Computational evidence

Protein change
AlphaMissense	0.5659	likely pathogenic
REVEL	0.693	pathogenic-leaning
SaProt	LLR -9.44	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.49 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.9, 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 0.00167% Admixed American · 1/60,032 alleles

Overall 6.84e-05% 1/1,461,778 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.Ser67Phe
Coding: c.200C>T
MANE Select: NM_000743
Type: single nucleotide variant
Location: chr15:78618798 (GRCh38)
Gene constraint: LOEUF 1.065 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.97 · 5 PDB
Residue 67: a β-strand

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

Disease context

SMOKING AS A QUANTITATIVE TRAIT LOCUS 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: urinary bladder, atony of

Similar variants

CHRNA3 p.Trp180Ter Likely pathogenic ★★ same condition
CHRNA3 p.Arg477His Uncertain significance ★★ ⚠ same condition
CHRNA3 p.Asn92Ser Uncertain significance ★★ ⚠ same condition
CHRNA3 p.Asp230Asn Uncertain significance ★★ ⚠ same condition
CHRNA3 p.Gly390Ala Uncertain significance ★★ ⚠ same condition
CHRNA3 p.Gly493Ala Uncertain significance ★★ ⚠ same condition
CHRNA3 p.Leu380Val Uncertain significance ★★ ⚠ same condition
CHRNA3 p.Pro498Leu 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-ser67phe (accessed [today's date]).

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