Is CNNM2 p.Pro254Ala (c.760C>G) pathogenic?

CNNM2 p.Pro254Ala (c.760C>G) is classified Uncertain significance in CNNM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-19). AlphaMissense: likely pathogenic (0.9752); Very rare (popmax 0.00133%, afr).

How common is CNNM2 p.Pro254Ala (c.760C>G) in the general population?

CNNM2 p.Pro254Ala (c.760C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CNNM2 p.Pro254Ala (c.760C>G)?

AlphaMissense predicts likely pathogenic (score 0.9752) — an in-silico prediction, not a clinical call.

CNNM2 p.Pro254Ala

c.760C>G · rs1420464428 · VCV1800548

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9752 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9752	likely pathogenic
REVEL	0.683	pathogenic-leaning
SaProt	LLR -10.60	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.5, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 412 bp · p 2.8e-23 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00133% African / African-American · 1/75,060 alleles

Overall 6.84e-05% 1/1,461,314 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: CNNM2
Protein: p.Pro254Ala
Coding: c.760C>G
MANE Select: NM_017649
dbSNP: rs1420464428
Type: single nucleotide variant
Location: chr10:102919240 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.70 · 7 PDB
Residue 254: the cnnm transmembrane domain

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

Similar variants

CNNM2 p.Pro254= Likely benign ★ 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
CNNM2 p.Ala44Val 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-pro254ala (accessed [today's date]).

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