Is CHRM3 p.Ser446= (c.1338A>G) pathogenic?

CHRM3 p.Ser446= (c.1338A>G) is classified Uncertain significance in CHRM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-10). Ultra-rare (popmax 0.0164%, mid); Associated with prune belly syndrome.

What condition is associated with CHRM3 p.Ser446= (c.1338A>G)?

CHRM3 p.Ser446= (c.1338A>G) is associated with prune belly syndrome (ClinVar).

How common is CHRM3 p.Ser446= (c.1338A>G) in the general population?

CHRM3 p.Ser446= (c.1338A>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

CHRM3 p.Ser446=

c.1338A>G · VCV3581838

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

prune belly syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -4.2
Overall
CADD	0.033	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00328% 53/1,613,974 alleles · ultra-rare exomes 46/1,461,872 · genomes 7/152,102 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.00667%	14,999
European (non-Finnish)	0.0039%	25,653
Remaining individualsnot grpmax-eligible	0.0032%	31,241

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.Ser446=
Coding: c.1338A>G
MANE Select: NM_001375978
Type: single nucleotide variant
Location: chr1:239908789 (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-ser446 (accessed [today's date]).

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