Is CNNM2 p.Ile40Val (c.118A>G) pathogenic?

CNNM2 p.Ile40Val (c.118A>G) is classified Conflicting classifications of pathogenicity in CNNM2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-06-24). AlphaMissense: likely benign (0.0683); Very rare (popmax 0.00139%, afr); Associated with hypomagnesemia, seizures, and intellectual disability 1.

What condition is associated with CNNM2 p.Ile40Val (c.118A>G)?

CNNM2 p.Ile40Val (c.118A>G) is associated with hypomagnesemia, seizures, and intellectual disability 1, renal hypomagnesemia 6 (ClinVar).

How common is CNNM2 p.Ile40Val (c.118A>G) in the general population?

CNNM2 p.Ile40Val (c.118A>G) is very rare (popmax 0.00139%, afr) (gnomAD).

What do computational predictors say about CNNM2 p.Ile40Val (c.118A>G)?

AlphaMissense predicts likely benign (score 0.0683) — an in-silico prediction, not a clinical call.

CNNM2 p.Ile40Val

c.118A>G · rs2134148877 · VCV1375331

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0683 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00139%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypomagnesemia, seizures, and intellectual disability 1

Computational evidence

Protein change
AlphaMissense	0.0683	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -4.29	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 -0.15	GERP -3.1, phastCons 0.035
Regional constraint	o/e 1.33	unconstrained · MANE · 150 bp · p 0.0044 · regional, not allelic
Overall
CADD	9.782	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 0.00139% African / African-American · 1/72,084 alleles

Overall 0.000142% 2/1,410,582 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00139%	72,084
European (non-Finnish)	8.64e-05%	1,157,342

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.Ile40Val
Coding: c.118A>G
MANE Select: NM_017649
dbSNP: rs2134148877
Type: single nucleotide variant
Location: chr10:102918598 (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

hypomagnesemia, seizures, and intellectual disability 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal hypomagnesemia 6

Similar variants

CNNM2 p.Ile40Asn Uncertain significance ★ ⚠ same residue
CNNM2 p.Ile40fs Pathogenic ★ same residue
CNNM2 p.Ile40= Likely benign ★ same residue
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

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-ile40val (accessed [today's date]).

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