Is CHRNB3 p.Arg231Cys (c.691C>T) pathogenic?

CHRNB3 p.Arg231Cys (c.691C>T) is classified Uncertain significance in CHRNB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely pathogenic (0.9889); Very rare (popmax 0.00144%, nfe).

How common is CHRNB3 p.Arg231Cys (c.691C>T) in the general population?

CHRNB3 p.Arg231Cys (c.691C>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about CHRNB3 p.Arg231Cys (c.691C>T)?

AlphaMissense predicts likely pathogenic (score 0.9889) — an in-silico prediction, not a clinical call.

CHRNB3 p.Arg231Cys

c.691C>T · VCV4228512

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9889 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9889	likely pathogenic · top 6% in CHRNB3
REVEL	0.923	moderately pathogenic-leaning
SaProt	LLR -13.92	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 3.4	GERP 1.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 39 kb · p 0.049 · regional, not allelic
Overall
CADD	27.6	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

Grpmax group 0.00144% European (non-Finnish) · 17/1,179,984 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00123% 18/1,461,732 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00144%	69,411
African / African-American	0.00134%	74,876

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.Arg231Cys
Coding: c.691C>T
MANE Select: NM_000749
Type: single nucleotide variant
Location: chr8:42731998 (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.Arg231Ser Uncertain significance ★ ⚠ same residue
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

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-arg231cys (accessed [today's date]).

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