Is CHRNB3 p.Lys375Arg (c.1124A>G) pathogenic?

CHRNB3 p.Lys375Arg (c.1124A>G) is classified Uncertain significance in CHRNB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-14). AlphaMissense: likely benign (0.0689); Ultra-rare (popmax 0.044%, afr).

How common is CHRNB3 p.Lys375Arg (c.1124A>G) in the general population?

CHRNB3 p.Lys375Arg (c.1124A>G) is ultra-rare (popmax 0.044%, afr) (gnomAD).

What do computational predictors say about CHRNB3 p.Lys375Arg (c.1124A>G)?

AlphaMissense predicts likely benign (score 0.0689) — an in-silico prediction, not a clinical call.

CHRNB3 p.Lys375Arg

c.1124A>G · rs372542634 · VCV2211181

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0689 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.044%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0689	likely benign
REVEL	0.251	benign-leaning
SaProt	LLR -6.92	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 2.3	GERP -0.18, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 39 kb · p 0.049 · regional, not allelic
Overall
CADD	5.617	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 0.044% African / African-American · 33/75,018 alleles

Filtering AF 0.0321% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0281%

Overall 0.00273% 44/1,614,146 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.044%	2,273
Admixed American	0.0133%	7,500
Remaining individualsnot grpmax-eligible	0.0032%	31,256
European (non-Finnish)	8.47e-05%	1,180,034

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.Lys375Arg
Coding: c.1124A>G
MANE Select: NM_000749
dbSNP: rs372542634
Type: single nucleotide variant
Location: chr8:42732431 (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.Ala396Ser 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-lys375arg (accessed [today's date]).

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