Is CHRNB1 p.Arg102Pro (c.305G>C) pathogenic?

CHRNB1 p.Arg102Pro (c.305G>C) is classified Conflicting classifications of pathogenicity in CHRNB1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-31). AlphaMissense: likely pathogenic (0.8662); Very rare (popmax 0.0022%, nfe); Associated with congenital myasthenic syndrome 2A.

What condition is associated with CHRNB1 p.Arg102Pro (c.305G>C)?

CHRNB1 p.Arg102Pro (c.305G>C) is associated with congenital myasthenic syndrome 2A, congenital myasthenic syndrome 4C (ClinVar).

How common is CHRNB1 p.Arg102Pro (c.305G>C) in the general population?

CHRNB1 p.Arg102Pro (c.305G>C) is very rare (popmax 0.0022%, nfe) (gnomAD).

What do computational predictors say about CHRNB1 p.Arg102Pro (c.305G>C)?

AlphaMissense predicts likely pathogenic (score 0.8662) — an in-silico prediction, not a clinical call.

CHRNB1 p.Arg102Pro

c.305G>C · rs201915086 · VCV325076

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8662 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 2A

Computational evidence

Protein change
AlphaMissense	0.8662	likely pathogenic
REVEL	0.904	moderately pathogenic-leaning
SaProt	LLR -11.86	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.051 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% European (non-Finnish) · 26/1,180,008 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.0128% 206/1,613,814 alleles · very rare exomes 186/1,461,640 · genomes 20/152,174 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.551%	182
Remaining individualsnot grpmax-eligible	0.0272%	3,675
European (non-Finnish)grpmax	0.0022%	45,385

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CHRNB1
Protein: p.Arg102Pro
Coding: c.305G>C
MANE Select: NM_000747
dbSNP: rs201915086
Type: single nucleotide variant
Location: chr17:7446894 (GRCh38)
Gene constraint: LOEUF 1.047 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.01 · 25 PDB
Residue 102: a β-strand

Full CHRNB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital myasthenic syndrome 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myasthenic syndrome 4C

Similar variants

CHRNB1 p.Arg102Cys Uncertain significance ★ ⚠ same residue
CHRNB1 p.Arg102Leu Uncertain significance ★ ⚠ same residue
CHRNB1 p.Arg102= Likely benign ★ same residue
CHRNB1 p.Arg243Cys Pathogenic/Likely pathogenic ★★ same condition
CHRNB1 p.Glu275Ter Pathogenic/Likely pathogenic ★★ same condition
CHRNB1 p.Val289Met Pathogenic ★★ ⚠ same condition
CHRNB1 c.1218-3C>T Uncertain significance ★★ same condition
CHRNB1 c.1365+5G>C 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/chrnb1-p-arg102pro (accessed [today's date]).

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