Is CHRNB2 p.Asp227Glu (c.681C>G) pathogenic?

CHRNB2 p.Asp227Glu (c.681C>G) is classified Uncertain significance in CHRNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). AlphaMissense: likely pathogenic (0.9236); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CHRNB2 p.Asp227Glu (c.681C>G)?

CHRNB2 p.Asp227Glu (c.681C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CHRNB2 p.Asp227Glu (c.681C>G) in the general population?

CHRNB2 p.Asp227Glu (c.681C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHRNB2 p.Asp227Glu (c.681C>G)?

AlphaMissense predicts likely pathogenic (score 0.9236) — an in-silico prediction, not a clinical call.

CHRNB2 p.Asp227Glu

c.681C>G · VCV4002658

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9236 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9236	likely pathogenic
REVEL	0.554	indeterminate
SaProt	LLR -11.47	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.55	GERP 2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 3,773 bp · p 1.9e-08 · regional, not allelic
Overall
CADD	21.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHRNB2
Protein: p.Asp227Glu
Coding: c.681C>G
MANE Select: NM_000748
Type: single nucleotide variant
Location: chr1:154571504 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 15 PDB
Residue 227: a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHRNB2 p.Ala2Ser Uncertain significance ★★ ⚠ same condition
CHRNB2 p.Arg3Trp Uncertain significance ★★ ⚠ same condition
CHRNB2 p.Asn392Lys Uncertain significance ★★ ⚠ same condition
CHRNB2 p.Gly430Ser Uncertain significance ★★ ⚠ same condition
CHRNB2 p.Ile434Met Uncertain significance ★★ ⚠ same condition
CHRNB2 p.Ser440Arg Uncertain significance ★★ ⚠ same condition
CHRNB2 p.Thr57Ile Uncertain significance ★★ ⚠ same condition
CHRNB2 p.Trp451Cys Uncertain significance ★★ ⚠ same condition

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-asp227glu (accessed [today's date]).

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