Is CHRM3 p.Pro506Arg (c.1517C>G) pathogenic?

CHRM3 p.Pro506Arg (c.1517C>G) is classified Uncertain significance in CHRM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely pathogenic (0.9979); Absent from gnomAD v4.1.

How common is CHRM3 p.Pro506Arg (c.1517C>G) in the general population?

CHRM3 p.Pro506Arg (c.1517C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHRM3 p.Pro506Arg (c.1517C>G)?

AlphaMissense predicts likely pathogenic (score 0.9979) — an in-silico prediction, not a clinical call.

CHRM3 p.Pro506Arg

c.1517C>G · VCV4228398

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9979 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9979	likely pathogenic · top 5% in CHRM3
REVEL	0.86	moderately pathogenic-leaning
SaProt	LLR -17.88	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 230 bp · p 1.6e-07 · regional, not allelic
Overall
CADD	28.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHRM3
Protein: p.Pro506Arg
Coding: c.1517C>G
MANE Select: NM_001375978
Type: single nucleotide variant
Location: chr1:239908968 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.30 · 5 PDB
Residue 506: an α-helix

Full CHRM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHRM3 p.Ala585Thr Uncertain significance ★★ ⚠ same type
CHRM3 p.Ala589Asp Uncertain significance ★★ ⚠ same type
CHRM3 p.Arg310His Uncertain significance ★★ ⚠ same type
CHRM3 p.Arg44Gln Uncertain significance ★★ ⚠ same type
CHRM3 p.Arg569Cys Uncertain significance ★★ ⚠ same type
CHRM3 p.Arg584His Uncertain significance ★★ ⚠ same type
CHRM3 p.Asn339Lys Uncertain significance ★★ ⚠ same type
CHRM3 p.Asn444Thr 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/chrm3-p-pro506arg (accessed [today's date]).

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