Is CHRNB3 p.Ala396Ser (c.1186G>T) pathogenic?

CHRNB3 p.Ala396Ser (c.1186G>T) is classified Uncertain significance in CHRNB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely benign (0.0975); Very rare (popmax 0.000339%, nfe).

How common is CHRNB3 p.Ala396Ser (c.1186G>T) in the general population?

CHRNB3 p.Ala396Ser (c.1186G>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CHRNB3 p.Ala396Ser (c.1186G>T)?

AlphaMissense predicts likely benign (score 0.0975) — an in-silico prediction, not a clinical call.

CHRNB3 p.Ala396Ser

c.1186G>T · rs1413044039 · VCV2250083

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0975 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0975	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -5.67	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 1	GERP -2, phastCons 0.001
Regional constraint	o/e 0.92	unconstrained · MANE · 39 kb · p 0.049 · regional, not allelic
Overall
CADD	15.79	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 0.000339% European (non-Finnish) · 4/1,179,526 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,611,354 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: CHRNB3
Protein: p.Ala396Ser
Coding: c.1186G>T
MANE Select: NM_000749
dbSNP: rs1413044039
Type: single nucleotide variant
Location: chr8:42732493 (GRCh38)
Gene constraint: LOEUF 1.066 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.65 · 1 PDB

Full CHRNB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHRNB3 p.Ile25= Benign ★★ same type
CHRNB3 p.Lys451Glu Benign ★★ ⚠ same type
CHRNB3 p.Ala147Val Uncertain significance ★ ⚠ same type
CHRNB3 p.Ala18Val Uncertain significance ★ ⚠ same type
CHRNB3 p.Ala206Thr Uncertain significance ★ ⚠ same type
CHRNB3 p.Ala26Thr Uncertain significance ★ ⚠ same type
CHRNB3 p.Ala31Asp Uncertain significance ★ ⚠ same type
CHRNB3 p.Arg213Gly Uncertain significance ★ ⚠ same type

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/chrnb3-p-ala396ser (accessed [today's date]).

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