Is CHRNB1 p.Val125Met (c.373G>A) pathogenic?

CHRNB1 p.Val125Met (c.373G>A) is classified Uncertain significance in CHRNB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-18). AlphaMissense: likely benign (0.3133); Very rare (popmax 0.00237%, nfe); Associated with congenital myasthenic syndrome 2A.

What condition is associated with CHRNB1 p.Val125Met (c.373G>A)?

CHRNB1 p.Val125Met (c.373G>A) is associated with congenital myasthenic syndrome 2A (ClinVar).

How common is CHRNB1 p.Val125Met (c.373G>A) in the general population?

CHRNB1 p.Val125Met (c.373G>A) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about CHRNB1 p.Val125Met (c.373G>A)?

AlphaMissense predicts likely benign (score 0.3133) — an in-silico prediction, not a clinical call.

CHRNB1 p.Val125Met

c.373G>A · rs148584502 · VCV1368438

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3133 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 2A

Computational evidence

Protein change
AlphaMissense	0.3133	likely benign
REVEL	0.697	pathogenic-leaning
SaProt	LLR -6.81	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -0.97, phastCons 0.91
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.051 · regional, not allelic
Overall
CADD	23.2	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 0.00237% European (non-Finnish) · 28/1,180,010 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.0018% 29/1,614,060 alleles · very rare exomes 27/1,461,860 · genomes 2/152,200 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00237%	42,143
African / African-American	0.00133%	74,926

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.Val125Met
Coding: c.373G>A
MANE Select: NM_000747
dbSNP: rs148584502
Type: single nucleotide variant
Location: chr17:7447062 (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-val125met (accessed [today's date]).

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