Is CHRM2 p.Ala158Val (c.473C>T) pathogenic?

CHRM2 p.Ala158Val (c.473C>T) is classified Uncertain significance in CHRM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-27). AlphaMissense: likely pathogenic (0.8293); Very rare (popmax 0.0011%, nfe).

How common is CHRM2 p.Ala158Val (c.473C>T) in the general population?

CHRM2 p.Ala158Val (c.473C>T) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about CHRM2 p.Ala158Val (c.473C>T)?

AlphaMissense predicts likely pathogenic (score 0.8293) — an in-silico prediction, not a clinical call.

CHRM2 p.Ala158Val

c.473C>T · VCV3603337

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8293 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8293	likely pathogenic
REVEL	0.207	benign-leaning
SaProt	LLR -10.84	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 133 bp · p 0.00013 · regional, not allelic
Overall
CADD	29.5	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 0.0011% European (non-Finnish) · 13/1,179,650 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00089% 13/1,461,378 alleles · very rare

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.Ala158Val
Coding: c.473C>T
MANE Select: NM_001006630
Type: single nucleotide variant
Location: chr7:137015338 (GRCh38)
Gene constraint: LOEUF 0.555 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 72.87 · 17 PDB
Residue 158: a disulfide bond; an α-helix

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

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-ala158val (accessed [today's date]).

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