Is CHRM3 p.Val281Asp (c.842T>A) pathogenic?

CHRM3 p.Val281Asp (c.842T>A) is classified Uncertain significance in CHRM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-12). AlphaMissense: likely benign (0.3273); Very rare (popmax 0.00134%, afr).

How common is CHRM3 p.Val281Asp (c.842T>A) in the general population?

CHRM3 p.Val281Asp (c.842T>A) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CHRM3 p.Val281Asp (c.842T>A)?

AlphaMissense predicts likely benign (score 0.3273) — an in-silico prediction, not a clinical call.

CHRM3 p.Val281Asp

c.842T>A · VCV4228392

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3273 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3273	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -6.29	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 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 703 bp · p 8.5e-17 · regional, not allelic
Overall
CADD	23.7	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 0.00134% African / African-American · 1/74,904 alleles

Overall 6.2e-05% 1/1,613,960 alleles · very rare exomes 0/1,461,824 · genomes 1/152,136 · joint denominator

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.Val281Asp
Coding: c.842T>A
MANE Select: NM_001375978
Type: single nucleotide variant
Location: chr1:239908293 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.30 · 5 PDB
Residue 281: a β-strand

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

Similar variants

CHRM3 p.Val281Ala Uncertain significance ★ ⚠ same residue
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

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-val281asp (accessed [today's date]).

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