Is CHRM3 p.Val414Met (c.1240G>A) pathogenic?

CHRM3 p.Val414Met (c.1240G>A) is classified Conflicting classifications of pathogenicity in CHRM3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-01-30). AlphaMissense: likely benign (0.0692); Ultra-rare (popmax 0.012%, afr); Associated with prune belly syndrome.

What condition is associated with CHRM3 p.Val414Met (c.1240G>A)?

CHRM3 p.Val414Met (c.1240G>A) is associated with prune belly syndrome (ClinVar).

How common is CHRM3 p.Val414Met (c.1240G>A) in the general population?

CHRM3 p.Val414Met (c.1240G>A) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about CHRM3 p.Val414Met (c.1240G>A)?

AlphaMissense predicts likely benign (score 0.0692) — an in-silico prediction, not a clinical call.

CHRM3 p.Val414Met

c.1240G>A · rs145638222 · VCV2077549

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0692 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

prune belly syndrome

Computational evidence

Protein change
AlphaMissense	0.0692	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -7.64	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 -4.1	GERP -4.2
Regional constraint	o/e 1.00	unconstrained · MANE · 569 bp · p 0.97 · regional, not allelic
Overall
CADD	0.161	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 0.012% African / African-American · 9/74,994 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.00552% 89/1,612,942 alleles · ultra-rare exomes 75/1,460,746 · genomes 14/152,196 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,333
Admixed American	0.01%	9,979
European (non-Finnish)	0.00602%	16,613
Remaining individualsnot grpmax-eligible	0.0032%	31,219
East Asian	0.00223%	44,816

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.Val414Met
Coding: c.1240G>A
MANE Select: NM_001375978
dbSNP: rs145638222
Type: single nucleotide variant
Location: chr1:239908691 (GRCh38)
Gene constraint: LOEUF 0.42 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.30 · 5 PDB

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

Disease context

prune belly syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHRM3 p.Ala585Thr Uncertain significance ★★ ⚠ same condition
CHRM3 p.Ala589Asp Uncertain significance ★★ ⚠ same condition
CHRM3 p.Arg310His Uncertain significance ★★ ⚠ same condition
CHRM3 p.Arg44Gln Uncertain significance ★★ ⚠ same condition
CHRM3 p.Arg569Cys Uncertain significance ★★ ⚠ same condition
CHRM3 p.Arg584His Uncertain significance ★★ ⚠ same condition
CHRM3 p.Asn444Thr Uncertain significance ★★ ⚠ same condition
CHRM3 p.Gln430His Uncertain significance ★★ ⚠ same condition

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-val414met (accessed [today's date]).

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