Is CHRM1 p.Val409Ile (c.1225G>A) pathogenic?

CHRM1 p.Val409Ile (c.1225G>A) is classified Uncertain significance in CHRM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely benign (0.1014); Very rare (popmax 0.00167%, amr).

How common is CHRM1 p.Val409Ile (c.1225G>A) in the general population?

CHRM1 p.Val409Ile (c.1225G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CHRM1 p.Val409Ile (c.1225G>A)?

AlphaMissense predicts likely benign (score 0.1014) — an in-silico prediction, not a clinical call.

CHRM1 p.Val409Ile

c.1225G>A · VCV4228387

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1014 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1014	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -3.62	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 6	GERP -1, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 229 bp · p 0.0001 · regional, not allelic
Overall
CADD	24.0	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 0.00167% Admixed American · 1/60,012 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000681% 11/1,614,100 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,012
European (non-Finnish)	0.000847%	118,005

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: CHRM1
Protein: p.Val409Ile
Coding: c.1225G>A
MANE Select: NM_000738
Type: single nucleotide variant
Location: chr11:62909876 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.51 · 7 PDB

Full CHRM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHRM1 p.Phe425Ser Likely pathogenic ★ same type
CHRM1 p.Ala26Asp Uncertain significance ★ ⚠ same type
CHRM1 p.Ala271Thr Uncertain significance ★ ⚠ same type
CHRM1 p.Arg137Cys Uncertain significance ★ ⚠ same type
CHRM1 p.Arg141Gln Uncertain significance ★ ⚠ same type
CHRM1 p.Arg213Gln Uncertain significance ★ ⚠ same type
CHRM1 p.Arg334His Uncertain significance ★ ⚠ same type
CHRM1 p.Arg336Gln 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/chrm1-p-val409ile (accessed [today's date]).

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