Is CHRM5 p.Pro144Arg (c.431C>G) pathogenic?

CHRM5 p.Pro144Arg (c.431C>G) is classified Uncertain significance in CHRM5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: ambiguous (0.5315); Very rare (popmax 8.47e-05%, nfe).

How common is CHRM5 p.Pro144Arg (c.431C>G) in the general population?

CHRM5 p.Pro144Arg (c.431C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CHRM5 p.Pro144Arg (c.431C>G)?

AlphaMissense predicts ambiguous (score 0.5315) — an in-silico prediction, not a clinical call.

CHRM5 p.Pro144Arg

c.431C>G · VCV4653566

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5315 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5315	ambiguous
REVEL	0.711	pathogenic-leaning
SaProt	LLR -8.44	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 1,595 bp · p 9.6e-08 · regional, not allelic
Overall
CADD	25.5	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 8.47e-05% European (non-Finnish) · 1/1,180,038 alleles

Overall 0.000657% 1/152,138 alleles · very rare

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: CHRM5
Protein: p.Pro144Arg
Coding: c.431C>G
MANE Select: NM_020371 · reported on NM_012125
Type: single nucleotide variant
Location: chr15:34063148 (GRCh38)

Full CHRM5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/chrm5-p-pro144arg (accessed [today's date]).

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