Is CHRM2 p.Ile39Phe (c.115A>T) pathogenic?

CHRM2 p.Ile39Phe (c.115A>T) is classified Uncertain significance in CHRM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-01). AlphaMissense: likely benign (0.213); Absent from gnomAD v4.1.

How common is CHRM2 p.Ile39Phe (c.115A>T) in the general population?

CHRM2 p.Ile39Phe (c.115A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHRM2 p.Ile39Phe (c.115A>T)?

AlphaMissense predicts likely benign (score 0.213) — an in-silico prediction, not a clinical call.

CHRM2 p.Ile39Phe

c.115A>T · rs2536203993 · VCV2286977

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.213 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.213	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -6.29	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 9.4	GERP 0.43, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 314 bp · p 0.0005 · regional, not allelic
Overall
CADD	25.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHRM2
Protein: p.Ile39Phe
Coding: c.115A>T
MANE Select: NM_001006630
dbSNP: rs2536203993
Type: single nucleotide variant
Location: chr7:137014980 (GRCh38)
Gene constraint: LOEUF 0.555 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 72.87 · 17 PDB
Residue 39: an α-helix

Full CHRM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHRM2 p.Ile39Asn Uncertain significance ★ ⚠ same residue
CHRM2 p.Ile39= Likely benign ★ same residue
CHRM2 p.Ala265Val Uncertain significance ★★ ⚠ same type
CHRM2 p.Arg52Cys Uncertain significance ★★ ⚠ same type
CHRM2 p.Gln358His Uncertain significance ★★ ⚠ same type
CHRM2 p.Glu305Gly Uncertain significance ★★ ⚠ same type
CHRM2 p.Gly238Ala Uncertain significance ★★ ⚠ same type
CHRM2 p.Gly254Val 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/chrm2-p-ile39phe (accessed [today's date]).

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