Is CHRNB2 p.Ala373Ser (c.1117G>T) pathogenic?

CHRNB2 p.Ala373Ser (c.1117G>T) is classified Uncertain significance in CHRNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-20). AlphaMissense: likely benign (0.0777); Very rare (popmax 8.67e-05%, nfe).

How common is CHRNB2 p.Ala373Ser (c.1117G>T) in the general population?

CHRNB2 p.Ala373Ser (c.1117G>T) is very rare (popmax 8.67e-05%, nfe) (gnomAD).

What do computational predictors say about CHRNB2 p.Ala373Ser (c.1117G>T)?

AlphaMissense predicts likely benign (score 0.0777) — an in-silico prediction, not a clinical call.

CHRNB2 p.Ala373Ser

c.1117G>T · rs778714852 · VCV1698259

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0777 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.67e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0777	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -7.78	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 -0.066	GERP 0.6, phastCons 0.93
Regional constraint	o/e 1.09	unconstrained · MANE · 4,110 bp · p 0.17 · regional, not allelic
Overall
CADD	9.779	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 8.67e-05% European (non-Finnish) · 1/1,153,256 alleles

Overall 7.15e-05% 1/1,398,518 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: CHRNB2
Protein: p.Ala373Ser
Coding: c.1117G>T
MANE Select: NM_000748
dbSNP: rs778714852
Type: single nucleotide variant
Location: chr1:154571940 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 15 PDB

Full CHRNB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHRNB2 p.Ala373Thr Uncertain significance ★★ ⚠ same residue
CHRNB2 p.Ala373= Likely benign ★★ same residue
CHRNB2 p.Val287Leu Pathogenic/Likely pathogenic ★★ ⚠ same type
CHRNB2 p.Val287Met Pathogenic ★★ ⚠ same type
CHRNB2 p.Val308Ala Pathogenic/Likely pathogenic ★★ same type
CHRNB2 c.1338+3G>T Uncertain significance ★★ same type
CHRNB2 c.366-3C>T Uncertain significance ★★ same type
CHRNB2 p.Ala135Val 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/chrnb2-p-ala373ser (accessed [today's date]).

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