Is CHRNB2 p.Phe403Cys (c.1208T>G) pathogenic?

CHRNB2 p.Phe403Cys (c.1208T>G) is classified Uncertain significance in CHRNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-12-18). AlphaMissense: likely benign (0.1165); Very rare (popmax 0.0098%, eas); Associated with Inborn genetic diseases.

What condition is associated with CHRNB2 p.Phe403Cys (c.1208T>G)?

CHRNB2 p.Phe403Cys (c.1208T>G) is associated with Inborn genetic diseases (ClinVar).

How common is CHRNB2 p.Phe403Cys (c.1208T>G) in the general population?

CHRNB2 p.Phe403Cys (c.1208T>G) is very rare (popmax 0.0098%, eas) (gnomAD).

What do computational predictors say about CHRNB2 p.Phe403Cys (c.1208T>G)?

AlphaMissense predicts likely benign (score 0.1165) — an in-silico prediction, not a clinical call.

CHRNB2 p.Phe403Cys

c.1208T>G · rs1696180621 · VCV1749370

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1165 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0098%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1165	likely benign
REVEL	0.282	benign-leaning
SaProt	LLR -5.32	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 0.26	GERP -3.4, phastCons 0.002
Regional constraint	o/e 1.09	unconstrained · MANE · 4,110 bp · p 0.17 · regional, not allelic
Overall
CADD	16.81	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 0.0098% East Asian · 4/40,812 alleles

Filtering AF 0.00328% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00194%

Overall 0.00029% 4/1,381,550 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.Phe403Cys
Coding: c.1208T>G
MANE Select: NM_000748
dbSNP: rs1696180621
Type: single nucleotide variant
Location: chr1:154572031 (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

Disease context

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

Similar variants

CHRNB2 p.Phe403Val Uncertain significance ★ ⚠ same residue
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

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-phe403cys (accessed [today's date]).

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