Is CNNM2 p.Ser365Phe (c.1094C>T) pathogenic?

CNNM2 p.Ser365Phe (c.1094C>T) is classified Benign in CNNM2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-01-22). AlphaMissense: likely pathogenic (0.9968); Absent from gnomAD v4.1; Associated with hypomagnesemia, seizures, and intellectual disability 1.

What condition is associated with CNNM2 p.Ser365Phe (c.1094C>T)?

CNNM2 p.Ser365Phe (c.1094C>T) is associated with hypomagnesemia, seizures, and intellectual disability 1 (ClinVar).

How common is CNNM2 p.Ser365Phe (c.1094C>T) in the general population?

CNNM2 p.Ser365Phe (c.1094C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNNM2 p.Ser365Phe (c.1094C>T)?

AlphaMissense predicts likely pathogenic (score 0.9968) — an in-silico prediction, not a clinical call.

CNNM2 p.Ser365Phe

c.1094C>T · rs1845549123 · VCV996057

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9968 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypomagnesemia, seizures, and intellectual disability 1

Computational evidence

Protein change
AlphaMissense	0.9968	likely pathogenic
REVEL	0.897	moderately pathogenic-leaning
SaProt	LLR -16.40	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 0.7, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 412 bp · p 2.8e-23 · regional, not allelic
Overall
CADD	34.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CNNM2
Protein: p.Ser365Phe
Coding: c.1094C>T
MANE Select: NM_017649
dbSNP: rs1845549123
Type: single nucleotide variant
Location: chr10:102919574 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.70 · 7 PDB
Residue 365: the cnnm transmembrane domain

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

Similar variants

CNNM2 p.Ser365= 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
CNNM2 p.Ala45Glu 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-ser365phe (accessed [today's date]).

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