Is CNNM2 p.Ala92Pro (c.274G>C) pathogenic?

CNNM2 p.Ala92Pro (c.274G>C) is classified Pathogenic in CNNM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-01). AlphaMissense: likely pathogenic (0.9376); Absent from gnomAD v4.1; Associated with hypomagnesemia, seizures, and intellectual disability 1.

What condition is associated with CNNM2 p.Ala92Pro (c.274G>C)?

CNNM2 p.Ala92Pro (c.274G>C) is associated with hypomagnesemia, seizures, and intellectual disability 1 (ClinVar).

How common is CNNM2 p.Ala92Pro (c.274G>C) in the general population?

CNNM2 p.Ala92Pro (c.274G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNNM2 p.Ala92Pro (c.274G>C)?

AlphaMissense predicts likely pathogenic (score 0.9376) — an in-silico prediction, not a clinical call.

CNNM2 p.Ala92Pro

c.274G>C · rs746369588 · VCV2578368

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9376 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypomagnesemia, seizures, and intellectual disability 1

Computational evidence

Protein change
AlphaMissense	0.9376	likely pathogenic ✓ concordant with ClinVar
REVEL	0.186	benign-leaning
SaProt	LLR -13.20	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 0.8, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 124 bp · p 0.0049 · regional, not allelic
Overall
CADD	22.3	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.Ala92Pro
Coding: c.274G>C
MANE Select: NM_017649
dbSNP: rs746369588
Type: single nucleotide variant
Location: chr10:102918754 (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

Similar variants

CNNM2 p.Ala92Thr Uncertain significance ★★ ⚠ same residue
CNNM2 p.Ala92fs Pathogenic ★★ 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

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-ala92pro (accessed [today's date]).

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