Is CHRM3 p.Val65Ile (c.193G>A) pathogenic?

CHRM3 p.Val65Ile (c.193G>A) is classified Benign in CHRM3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.0669); Low-frequency (popmax 4.28%, sas).

How common is CHRM3 p.Val65Ile (c.193G>A) in the general population?

CHRM3 p.Val65Ile (c.193G>A) is low-frequency (popmax 4.28%, sas) (gnomAD).

What do computational predictors say about CHRM3 p.Val65Ile (c.193G>A)?

AlphaMissense predicts likely benign (score 0.0669) — an in-silico prediction, not a clinical call.

CHRM3 p.Val65Ile

c.193G>A · rs2067481 · VCV1576872

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0669 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.28%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0669	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -7.03	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.1	GERP -4.2
Regional constraint	o/e 0.52	unconstrained · MANE · 703 bp · p 8.5e-17 · regional, not allelic
Overall
CADD	0.281	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 4.28% South Asian · 3,897/91,082 alleles

Filtering AF 4.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.12%

Overall 1.56% 25,154/1,614,116 alleles · low-frequency exomes 23,099/1,461,886 · genomes 2,055/152,230 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	4.28%	23
Finnishnot grpmax-eligible	4.26%	23
Middle Eastern	2.21%	45
Remaining individualsnot grpmax-eligible	1.45%	69
European (non-Finnish)	1.41%	71
Ashkenazi Jewishnot grpmax-eligible	0.868%	115
Admixed American	0.488%	205
African / African-American	0.255%	393
East Asian	0.238%	419

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: CHRM3
Protein: p.Val65Ile
Coding: c.193G>A
MANE Select: NM_001375978
dbSNP: rs2067481
Type: single nucleotide variant
Location: chr1:239907644 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.30 · 5 PDB
Residue 65: a UniProt-annotated variant site (in); 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-val65ile (accessed [today's date]).

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