Is CNNM2 p.Ser145Gly (c.433A>G) pathogenic?

CNNM2 p.Ser145Gly (c.433A>G) is classified Conflicting classifications of pathogenicity in CNNM2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-05-24). AlphaMissense: likely benign (0.0562); Ultra-rare (popmax 0.0855%, afr); Associated with Inborn genetic diseases.

What condition is associated with CNNM2 p.Ser145Gly (c.433A>G)?

CNNM2 p.Ser145Gly (c.433A>G) is associated with Inborn genetic diseases, renal hypomagnesemia 6, hypomagnesemia, seizures, and intellectual disability 1 (ClinVar).

How common is CNNM2 p.Ser145Gly (c.433A>G) in the general population?

CNNM2 p.Ser145Gly (c.433A>G) is ultra-rare (popmax 0.0855%, afr) (gnomAD).

What do computational predictors say about CNNM2 p.Ser145Gly (c.433A>G)?

AlphaMissense predicts likely benign (score 0.0562) — an in-silico prediction, not a clinical call.

CNNM2 p.Ser145Gly

c.433A>G · rs371028392 · VCV2194751

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0562 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0855%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0562	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -6.24	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 7.8	GERP 0.19, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 310 bp · p 2.5e-05 · regional, not allelic
Overall
CADD	20.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0855% African / African-American · 64/74,824 alleles

Filtering AF 0.0687% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0626%

Overall 0.00441% 71/1,611,572 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0855%	1,169
Admixed American	0.005%	19,985
Remaining individualsnot grpmax-eligible	0.00481%	20,793
European (non-Finnish)	8.48e-05%	1,179,165

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.Ser145Gly
Coding: c.433A>G
MANE Select: NM_017649
dbSNP: rs371028392
Type: single nucleotide variant
Location: chr10:102918913 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.70 · 7 PDB
Residue 145: the 'disordered' region

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

Also linked: renal hypomagnesemia 6 hypomagnesemia, seizures, and intellectual disability 1

Similar variants

CNNM2 p.Arg602Ter Likely pathogenic ★★ same condition
CNNM2 p.Glu122Lys Pathogenic/Likely pathogenic ★★ same condition
CNNM2 p.Glu357Lys Pathogenic ★★ same condition
CNNM2 p.Ser269Trp Pathogenic/Likely pathogenic ★★ same condition
CNNM2 c.1904-6C>G Uncertain significance ★★ same condition
CNNM2 p.Ala45Glu Uncertain significance ★★ ⚠ same condition
CNNM2 p.Ala45Ser Uncertain significance ★★ ⚠ same condition
CNNM2 p.Ala671Val 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-ser145gly (accessed [today's date]).

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