Is CHRNB3 p.Arg91Cys (c.271C>T) pathogenic?

CHRNB3 p.Arg91Cys (c.271C>T) is classified Uncertain significance in CHRNB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-08). AlphaMissense: likely benign (0.0867); Ultra-rare (popmax 0.0829%, mid).

How common is CHRNB3 p.Arg91Cys (c.271C>T) in the general population?

CHRNB3 p.Arg91Cys (c.271C>T) is ultra-rare (popmax 0.0829%, mid) (gnomAD).

What do computational predictors say about CHRNB3 p.Arg91Cys (c.271C>T)?

AlphaMissense predicts likely benign (score 0.0867) — an in-silico prediction, not a clinical call.

CHRNB3 p.Arg91Cys

c.271C>T · VCV4002663

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0867 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0829%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0867	likely benign
REVEL	0.478	indeterminate
SaProt	LLR -9.53	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 -0.64	GERP 0.13
Regional constraint	o/e 0.92	unconstrained · MANE · 39 kb · p 0.049 · regional, not allelic
Overall
CADD	23.1	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 0.0829% Middle Eastern · 5/6,030 alleles

Filtering AF 0.0326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0211%

Overall 0.00249% 40/1,603,916 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0829%	1,206
East Asian	0.00897%	11,144
Remaining individualsnot grpmax-eligible	0.00483%	20,683
European (non-Finnish)	0.00213%	46,958
Admixed American	0.00169%	59,132
African / African-American	0.00134%	74,570
South Asian	0.00112%	89,530

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.Arg91Cys
Coding: c.271C>T
MANE Select: NM_000749
Type: single nucleotide variant
Location: chr8:42730615 (GRCh38)
Gene constraint: LOEUF 1.066 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.65 · 1 PDB
Residue 91: a β-strand

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

Similar variants

CHRNB3 p.Arg91His 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-arg91cys (accessed [today's date]).

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