Is CHRM2 p.Pro378Leu (c.1133C>T) pathogenic?

CHRM2 p.Pro378Leu (c.1133C>T) is classified Uncertain significance in CHRM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). AlphaMissense: likely benign (0.0986); Very rare (popmax 0.00223%, eas); Associated with dilated cardiomyopathy 1A.

What condition is associated with CHRM2 p.Pro378Leu (c.1133C>T)?

CHRM2 p.Pro378Leu (c.1133C>T) is associated with dilated cardiomyopathy 1A (ClinVar).

How common is CHRM2 p.Pro378Leu (c.1133C>T) in the general population?

CHRM2 p.Pro378Leu (c.1133C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CHRM2 p.Pro378Leu (c.1133C>T)?

AlphaMissense predicts likely benign (score 0.0986) — an in-silico prediction, not a clinical call.

CHRM2 p.Pro378Leu

Q: How is Familial dilated cardiomyopathy with conduction defect due to LMNA mutation inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1133C>T · VCV3778835

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dilated cardiomyopathy 1A

Computational evidence

Protein change
AlphaMissense	0.0986	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -7.89	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 0.47	GERP 2.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 646 bp · p 0.96 · regional, not allelic
Overall
CADD	21.6	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 0.00223% East Asian · 1/44,782 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000753% 11/1,461,116 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,570
Remaining individualsnot grpmax-eligible	0.0032%	31,227
East Asiangrpmax	0.00223%	44,782
South Asian	0.0011%	91,054
European (non-Finnish)	0.000509%	196,574

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: CHRM2
Protein: p.Pro378Leu
Coding: c.1133C>T
MANE Select: NM_001006630
Type: single nucleotide variant
Location: chr7:137015998 (GRCh38)
Gene constraint: LOEUF 0.555 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 72.87 · 17 PDB
Residue 378: an α-helix

Full CHRM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dilated cardiomyopathy 1A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial dilated cardiomyopathy with conduction defect due to LMNA mutation (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

CHRM2 p.Ala265Val Uncertain significance ★★ ⚠ same type
CHRM2 p.Arg52Cys Uncertain significance ★★ ⚠ same type
CHRM2 p.Gln358His Uncertain significance ★★ ⚠ same type
CHRM2 p.Glu305Gly Uncertain significance ★★ ⚠ same type
CHRM2 p.Gly238Ala Uncertain significance ★★ ⚠ same type
CHRM2 p.Gly254Val Uncertain significance ★★ ⚠ same type
CHRM2 p.Gly277Glu Uncertain significance ★★ ⚠ same type
CHRM2 p.Ile325Phe Uncertain significance ★★ ⚠ same type

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/chrm2-p-pro378leu (accessed [today's date]).

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