Is CHRNB1 p.Pro409Ala (c.1225C>G) pathogenic?

CHRNB1 p.Pro409Ala (c.1225C>G) is classified Conflicting classifications of pathogenicity in CHRNB1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0689); Rare (popmax 0.312%, sas); Associated with congenital myasthenic syndrome 2A.

What condition is associated with CHRNB1 p.Pro409Ala (c.1225C>G)?

CHRNB1 p.Pro409Ala (c.1225C>G) is associated with congenital myasthenic syndrome 2A, congenital myasthenic syndrome 4C (ClinVar).

How common is CHRNB1 p.Pro409Ala (c.1225C>G) in the general population?

CHRNB1 p.Pro409Ala (c.1225C>G) is rare (popmax 0.312%, sas) (gnomAD).

What do computational predictors say about CHRNB1 p.Pro409Ala (c.1225C>G)?

AlphaMissense predicts likely benign (score 0.0689) — an in-silico prediction, not a clinical call.

CHRNB1 p.Pro409Ala

c.1225C>G · rs202144045 · VCV325107

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0689 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.312%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 2A

Computational evidence

Protein change
AlphaMissense	0.0689	likely benign
REVEL	0.22	benign-leaning
SaProt	LLR -6.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.25	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.55	GERP 0.14, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.051 · regional, not allelic
Overall
CADD	21.5	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 0.312% South Asian · 284/91,086 alleles

Filtering AF 0.282% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.27%

Overall 0.0284% 458/1,614,174 alleles · rare exomes 436/1,461,892 · genomes 22/152,282 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.312%	321
Ashkenazi Jewishnot grpmax-eligible	0.203%	493
Middle Eastern	0.115%	866
Remaining individualsnot grpmax-eligible	0.0496%	2,016
Admixed American	0.0333%	3,001
European (non-Finnish)	0.00449%	22,265
African / African-American	0.004%	25,009

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.Pro409Ala
Coding: c.1225C>G
MANE Select: NM_000747
dbSNP: rs202144045
Type: single nucleotide variant
Location: chr17:7455801 (GRCh38)
Gene constraint: LOEUF 1.047 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.01 · 25 PDB

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.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
CHRNB1 c.*512C>T Uncertain significance ★★ same condition
CHRNB1 p.Ala105Val Uncertain significance ★★ ⚠ same condition
CHRNB1 p.Ala15Val 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-pro409ala (accessed [today's date]).

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