Is CHRM5 p.Ala269Pro (c.805G>C) pathogenic?

CHRM5 p.Ala269Pro (c.805G>C) is classified Uncertain significance in CHRM5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely benign (0.1027); Ultra-rare (popmax 0.0373%, afr).

How common is CHRM5 p.Ala269Pro (c.805G>C) in the general population?

CHRM5 p.Ala269Pro (c.805G>C) is ultra-rare (popmax 0.0373%, afr) (gnomAD).

What do computational predictors say about CHRM5 p.Ala269Pro (c.805G>C)?

AlphaMissense predicts likely benign (score 0.1027) — an in-silico prediction, not a clinical call.

CHRM5 p.Ala269Pro

c.805G>C · VCV4228413

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1027 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0373%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1027	likely benign
REVEL	0.298	indeterminate
SaProt	LLR -6.30	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.83, phastCons 0.99
Regional constraint	o/e 0.79	unconstrained · MANE · 1,595 bp · p 9.6e-08 · regional, not allelic
Overall
CADD	19.84	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 0.0373% African / African-American · 28/75,044 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0229%

Overall 0.00198% 32/1,613,674 alleles · ultra-rare exomes 17/1,461,376 · genomes 15/152,298 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0373%	2,680
Admixed American	0.00333%	30,013
Remaining individualsnot grpmax-eligible	0.0032%	31,253

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.Ala269Pro
Coding: c.805G>C
MANE Select: NM_012125
Type: single nucleotide variant
Location: chr15:34063522 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI 0.09 (gnomAD)
Structure: AlphaFold pLDDT 69.14 · 2 PDB
Residue 269: the 'disordered' region

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

Similar variants

CHRM5 p.Glu412Lys Benign ★★ same type
CHRM5 p.Pro191= Benign ★★ same type
CHRM5 p.Ala165Thr Uncertain significance ★ ⚠ same type
CHRM5 p.Ala339Val Uncertain significance ★ ⚠ same type
CHRM5 p.Ala366Thr Uncertain significance ★ ⚠ same type
CHRM5 p.Ala441Val Uncertain significance ★ ⚠ same type
CHRM5 p.Ala9Gly Uncertain significance ★ ⚠ same type
CHRM5 p.Arg128His 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/chrm5-p-ala269pro (accessed [today's date]).

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