Is CHRM2 p.Val231Ile (c.691G>A) pathogenic?

CHRM2 p.Val231Ile (c.691G>A) is classified Benign/Likely benign in CHRM2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.0731); Rare (popmax 0.663%, nfe).

How common is CHRM2 p.Val231Ile (c.691G>A) in the general population?

CHRM2 p.Val231Ile (c.691G>A) is rare (popmax 0.663%, nfe) (gnomAD).

What do computational predictors say about CHRM2 p.Val231Ile (c.691G>A)?

AlphaMissense predicts likely benign (score 0.0731) — an in-silico prediction, not a clinical call.

CHRM2 p.Val231Ile

c.691G>A · rs76394680 · VCV227248

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0731 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.663%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0731	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -6.92	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 12	GERP 2.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 646 bp · p 0.96 · regional, not allelic
Overall
CADD	20.9	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 0.663% European (non-Finnish) · 7,822/1,179,492 alleles

Filtering AF 0.651% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.646%

Overall 0.547% 8,819/1,612,814 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.663%	151
Remaining individualsnot grpmax-eligible	0.605%	165
Ashkenazi Jewishnot grpmax-eligible	0.47%	213
Finnishnot grpmax-eligible	0.441%	227
Admixed American	0.135%	739
African / African-American	0.111%	903
East Asian	0.0605%	1,652
Middle Eastern	0.0495%	2,019
South Asian	0.00439%	22,766

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.Val231Ile
Coding: c.691G>A
MANE Select: NM_001006630
dbSNP: rs76394680
Type: single nucleotide variant
Location: chr7:137015556 (GRCh38)
Gene constraint: LOEUF 0.555 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 72.87 · 17 PDB
Residue 231: the 'disordered' region

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

Similar variants

CHRM2 p.Val231Ala Uncertain significance ★ ⚠ same residue
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

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-val231ile (accessed [today's date]).

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