Is CNNM2 p.Ala45Ser (c.133G>T) pathogenic?

CNNM2 p.Ala45Ser (c.133G>T) is classified Uncertain significance in CNNM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-03). AlphaMissense: likely benign (0.0979); Very rare (popmax 0.00339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CNNM2 p.Ala45Ser (c.133G>T)?

CNNM2 p.Ala45Ser (c.133G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CNNM2 p.Ala45Ser (c.133G>T) in the general population?

CNNM2 p.Ala45Ser (c.133G>T) is very rare (popmax 0.00339%, nfe) (gnomAD).

What do computational predictors say about CNNM2 p.Ala45Ser (c.133G>T)?

AlphaMissense predicts likely benign (score 0.0979) — an in-silico prediction, not a clinical call.

CNNM2 p.Ala45Ser

c.133G>T · rs755515176 · VCV2333986

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0979 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0979	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -8.08	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 8.2	GERP 0.58, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 150 bp · p 0.0044 · regional, not allelic
Overall
CADD	18.87	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 0.00339% European (non-Finnish) · 39/1,149,302 alleles

Filtering AF 0.00254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00223%

Overall 0.00293% 41/1,397,396 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00339%	29,469
Remaining individualsnot grpmax-eligible	0.00333%	29,993

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.Ala45Ser
Coding: c.133G>T
MANE Select: NM_017649
dbSNP: rs755515176
Type: single nucleotide variant
Location: chr10:102918613 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNNM2 p.Ala45Glu Uncertain significance ★★ ⚠ same residue
CNNM2 p.Arg153His Uncertain significance ★★ ⚠ same condition
CNNM2 p.Arg30Cys Uncertain significance ★★ ⚠ same condition
CNNM2 p.Arg679Cys Uncertain significance ★★ ⚠ same condition
CNNM2 p.Arg679His Uncertain significance ★★ ⚠ same condition
CNNM2 p.Asn657Ser Uncertain significance ★★ ⚠ same condition
CNNM2 p.Asn680Ser Uncertain significance ★★ ⚠ same condition
CNNM2 p.Gln826Pro Uncertain significance ★★ ⚠ same condition

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-ala45ser (accessed [today's date]).

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