Is CHRNA3 p.Ser388Phe (c.1163C>T) pathogenic?

CHRNA3 p.Ser388Phe (c.1163C>T) is classified Likely benign in CHRNA3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-13). AlphaMissense: likely benign (0.1205); Rare (popmax 0.429%, mid); Associated with SMOKING AS A QUANTITATIVE TRAIT LOCUS 3.

What condition is associated with CHRNA3 p.Ser388Phe (c.1163C>T)?

CHRNA3 p.Ser388Phe (c.1163C>T) is associated with SMOKING AS A QUANTITATIVE TRAIT LOCUS 3, urinary bladder, atony of (ClinVar).

How common is CHRNA3 p.Ser388Phe (c.1163C>T) in the general population?

CHRNA3 p.Ser388Phe (c.1163C>T) is rare (popmax 0.429%, mid) (gnomAD).

What do computational predictors say about CHRNA3 p.Ser388Phe (c.1163C>T)?

AlphaMissense predicts likely benign (score 0.1205) — an in-silico prediction, not a clinical call.

CHRNA3 p.Ser388Phe

c.1163C>T · rs71581734 · VCV2066696

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1205 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.429%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

SMOKING AS A QUANTITATIVE TRAIT LOCUS 3

Computational evidence

Protein change
AlphaMissense	0.1205	likely benign
REVEL	0.427	indeterminate
SaProt	LLR -7.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 0.84, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 24 kb · p 0.00014 · regional, not allelic
Overall
CADD	16.41	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 0.429% Middle Eastern · 26/6,062 alleles

Filtering AF 0.301% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.258%

Overall 0.0215% 347/1,614,112 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.429%	233
South Asian	0.234%	428
Remaining individualsnot grpmax-eligible	0.0352%	2,841
Admixed American	0.0133%	7,500
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
European (non-Finnish)	0.00627%	15,946
East Asian	0.00223%	44,868
African / African-American	0.00133%	75,016

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.Ser388Phe
Coding: c.1163C>T
MANE Select: NM_000743
dbSNP: rs71581734
Type: single nucleotide variant
Location: chr15:78601479 (GRCh38)
Gene constraint: LOEUF 1.065 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.97 · 5 PDB
Residue 388: 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)

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-ser388phe (accessed [today's date]).

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