Is CHRNB1 p.Ser412Pro (c.1234T>C) pathogenic?

CHRNB1 p.Ser412Pro (c.1234T>C) is classified Uncertain significance in CHRNB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-07). AlphaMissense: likely benign (0.0547); Very rare (popmax 0.000254%, nfe); Associated with congenital myasthenic syndrome 2A.

What condition is associated with CHRNB1 p.Ser412Pro (c.1234T>C)?

CHRNB1 p.Ser412Pro (c.1234T>C) is associated with congenital myasthenic syndrome 2A (ClinVar).

How common is CHRNB1 p.Ser412Pro (c.1234T>C) in the general population?

CHRNB1 p.Ser412Pro (c.1234T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CHRNB1 p.Ser412Pro (c.1234T>C)?

AlphaMissense predicts likely benign (score 0.0547) — an in-silico prediction, not a clinical call.

CHRNB1 p.Ser412Pro

c.1234T>C · rs2069943964 · VCV2907166

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0547 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 2A

Computational evidence

Protein change
AlphaMissense	0.0547	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -5.65	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 0.18	GERP -4.7, phastCons 0.014
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.051 · regional, not allelic
Overall
CADD	2.339	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 0.000254% European (non-Finnish) · 3/1,180,032 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,174 alleles · very rare exomes 3/1,461,888 · genomes 0/152,286 · joint denominator

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.Ser412Pro
Coding: c.1234T>C
MANE Select: NM_000747
dbSNP: rs2069943964
Type: single nucleotide variant
Location: chr17:7455810 (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

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 p.Ala105Val Uncertain significance ★★ ⚠ same condition
CHRNB1 p.Ala15Val Uncertain significance ★★ ⚠ same condition
CHRNB1 p.Ala18Gly 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-ser412pro (accessed [today's date]).

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