Is CHRNE p.Pro41Ser (c.121C>T) pathogenic?

CHRNE p.Pro41Ser (c.121C>T) is classified Uncertain significance in CHRNE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-06). AlphaMissense: likely pathogenic (0.9723); Very rare (popmax 0.000932%, nfe); Associated with congenital myasthenic syndrome 4A.

What condition is associated with CHRNE p.Pro41Ser (c.121C>T)?

CHRNE p.Pro41Ser (c.121C>T) is associated with congenital myasthenic syndrome 4A (ClinVar).

How common is CHRNE p.Pro41Ser (c.121C>T) in the general population?

CHRNE p.Pro41Ser (c.121C>T) is very rare (popmax 0.000932%, nfe) (gnomAD).

What do computational predictors say about CHRNE p.Pro41Ser (c.121C>T)?

AlphaMissense predicts likely pathogenic (score 0.9723) — an in-silico prediction, not a clinical call.

CHRNE p.Pro41Ser

c.121C>T · rs2507563560 · VCV2738400

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9723 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 4A

Computational evidence

Protein change
AlphaMissense	0.9723	likely pathogenic
REVEL	0.942	strongly pathogenic-leaning
SaProt	LLR -10.59	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 4,324 bp · p 7.4e-05 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000932% European (non-Finnish) · 11/1,180,018 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000821% 12/1,461,874 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)grpmax	0.000932%	107,274

Remaining individuals 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: CHRNE
Protein: p.Pro41Ser
Coding: c.121C>T
MANE Select: NM_001145536 · reported on NM_000080
dbSNP: rs2507563560
Type: single nucleotide variant
Location: chr17:4902689 (GRCh38)

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

Disease context

congenital myasthenic syndrome 4A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/chrne-p-pro41ser (accessed [today's date]).

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