Is CNNM2 p.Pro227Arg (c.680C>G) pathogenic?

CNNM2 p.Pro227Arg (c.680C>G) is classified Uncertain significance in CNNM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-24). AlphaMissense: likely benign (0.1729); Absent from gnomAD v4.1.

How common is CNNM2 p.Pro227Arg (c.680C>G) in the general population?

CNNM2 p.Pro227Arg (c.680C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNNM2 p.Pro227Arg (c.680C>G)?

AlphaMissense predicts likely benign (score 0.1729) — an in-silico prediction, not a clinical call.

CNNM2 p.Pro227Arg

c.680C>G · rs2134149942 · VCV1477284

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1729 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1729	likely benign
REVEL	0.393	indeterminate
SaProt	LLR -7.86	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 310 bp · p 2.5e-05 · regional, not allelic
Overall
CADD	25.3	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: CNNM2
Protein: p.Pro227Arg
Coding: c.680C>G
MANE Select: NM_017649
dbSNP: rs2134149942
Type: single nucleotide variant
Location: chr10:102919160 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.70 · 7 PDB

Full CNNM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNNM2 p.Pro227= Likely benign ★ same residue
CNNM2 p.Pro227del Uncertain significance ★ same residue
CNNM2 p.Arg602Ter Likely pathogenic ★★ same type
CNNM2 p.Asn327Ser Likely pathogenic ★★ same type
CNNM2 p.Glu122Lys Pathogenic/Likely pathogenic ★★ same type
CNNM2 p.Glu357Lys Pathogenic ★★ same type
CNNM2 p.Ser269Trp Pathogenic/Likely pathogenic ★★ same type
CNNM2 c.1904-6C>G 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/cnnm2-p-pro227arg (accessed [today's date]).

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