Is CHRNB3 p.Val105Ile (c.313G>A) pathogenic?

CHRNB3 p.Val105Ile (c.313G>A) is classified Uncertain significance in CHRNB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-11). AlphaMissense: likely benign (0.115); Very rare (popmax 0.00365%, nfe).

How common is CHRNB3 p.Val105Ile (c.313G>A) in the general population?

CHRNB3 p.Val105Ile (c.313G>A) is very rare (popmax 0.00365%, nfe) (gnomAD).

What do computational predictors say about CHRNB3 p.Val105Ile (c.313G>A)?

AlphaMissense predicts likely benign (score 0.115) — an in-silico prediction, not a clinical call.

CHRNB3 p.Val105Ile

c.313G>A · rs377712071 · VCV2282617

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.115 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00365%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.115	likely benign
REVEL	0.405	indeterminate
SaProt	LLR -7.07	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 8.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 39 kb · p 0.049 · regional, not allelic
Overall
CADD	24.0	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 0.00365% European (non-Finnish) · 43/1,178,246 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00279% 45/1,611,182 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00365%	27,401
Remaining individualsnot grpmax-eligible	0.0016%	62,376
African / African-American	0.00134%	74,744

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.Val105Ile
Coding: c.313G>A
MANE Select: NM_000749
dbSNP: rs377712071
Type: single nucleotide variant
Location: chr8:42730657 (GRCh38)
Gene constraint: LOEUF 1.066 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.65 · 1 PDB
Residue 105: a β-strand

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

Similar variants

CHRNB3 p.Val105Ala Uncertain significance ★ ⚠ same residue
CHRNB3 p.Val105Phe 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

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-val105ile (accessed [today's date]).

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