Is CHRM2 p.Asp253Asn (c.757G>A) pathogenic?

CHRM2 p.Asp253Asn (c.757G>A) is classified Likely benign in CHRM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0686); Rare (popmax 0.115%, afr).

How common is CHRM2 p.Asp253Asn (c.757G>A) in the general population?

CHRM2 p.Asp253Asn (c.757G>A) is rare (popmax 0.115%, afr) (gnomAD).

What do computational predictors say about CHRM2 p.Asp253Asn (c.757G>A)?

AlphaMissense predicts likely benign (score 0.0686) — an in-silico prediction, not a clinical call.

CHRM2 p.Asp253Asn

c.757G>A · rs140681489 · VCV706948

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0686 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0686	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -5.50	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 3.3	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 646 bp · p 0.96 · regional, not allelic
Overall
CADD	16.17	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 0.115% African / African-American · 86/74,878 alleles

Filtering AF 0.0952% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.088%

Overall 0.00781% 126/1,612,858 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.115%	871
Remaining individualsnot grpmax-eligible	0.024%	4,163
Middle Eastern	0.0165%	6,054
South Asian	0.00549%	18,211
Admixed American	0.00501%	19,951
European (non-Finnish)	0.00136%	73,719

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.Asp253Asn
Coding: c.757G>A
MANE Select: NM_001006630
dbSNP: rs140681489
Type: single nucleotide variant
Location: chr7:137015622 (GRCh38)
Gene constraint: LOEUF 0.555 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 72.87 · 17 PDB
Residue 253: the 'disordered' region

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-asp253asn (accessed [today's date]).

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