Is CNNM2 p.Leu725Phe (c.2175G>C) pathogenic?

CNNM2 p.Leu725Phe (c.2175G>C) is classified Uncertain significance in CNNM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-08). AlphaMissense: likely benign (0.2296); Very rare (popmax 0.0011%, sas); Associated with hypomagnesemia, seizures, and intellectual disability 1.

What condition is associated with CNNM2 p.Leu725Phe (c.2175G>C)?

CNNM2 p.Leu725Phe (c.2175G>C) is associated with hypomagnesemia, seizures, and intellectual disability 1, renal hypomagnesemia 6 (ClinVar).

How common is CNNM2 p.Leu725Phe (c.2175G>C) in the general population?

CNNM2 p.Leu725Phe (c.2175G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CNNM2 p.Leu725Phe (c.2175G>C)?

AlphaMissense predicts likely benign (score 0.2296) — an in-silico prediction, not a clinical call.

CNNM2 p.Leu725Phe

c.2175G>C · VCV3590489

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2296 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypomagnesemia, seizures, and intellectual disability 1

Computational evidence

Protein change
AlphaMissense	0.2296	likely benign
REVEL	0.236	benign-leaning
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 8,525 bp · p 0.026 · regional, not allelic
Overall
CADD	24.8	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 0.0011% South Asian · 1/91,068 alleles

Overall 0.000205% 3/1,461,608 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	63,968
South Asiangrpmax	0.0011%	91,068
European (non-Finnish)	8.48e-05%	1,179,788

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu725Phe
Coding: c.2175G>C
MANE Select: NM_017649
Type: single nucleotide variant
Location: chr10:103071781 (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.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.Ala671Val Uncertain significance ★★ ⚠ same condition
CNNM2 p.Ala874Thr 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-leu725phe (accessed [today's date]).

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