Is CNNM2 p.Ala92Thr (c.274G>A) pathogenic?

CNNM2 p.Ala92Thr (c.274G>A) is classified Uncertain significance in CNNM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-24). AlphaMissense: likely benign (0.1695); Very rare (popmax 0.0057%, sas); Associated with renal hypomagnesemia 6.

What condition is associated with CNNM2 p.Ala92Thr (c.274G>A)?

CNNM2 p.Ala92Thr (c.274G>A) is associated with renal hypomagnesemia 6, hypomagnesemia, seizures, and intellectual disability 1 (ClinVar).

How common is CNNM2 p.Ala92Thr (c.274G>A) in the general population?

CNNM2 p.Ala92Thr (c.274G>A) is very rare (popmax 0.0057%, sas) (gnomAD).

What do computational predictors say about CNNM2 p.Ala92Thr (c.274G>A)?

AlphaMissense predicts likely benign (score 0.1695) — an in-silico prediction, not a clinical call.

CNNM2 p.Ala92Thr

c.274G>A · VCV3494414

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1695 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0057%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

renal hypomagnesemia 6

Computational evidence

Protein change
AlphaMissense	0.1695	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -4.60	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 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	22.8	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 0.0057% South Asian · 5/87,658 alleles

Filtering AF 0.00233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00204%

Overall 0.00264% 42/1,592,214 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0057%	17,532
European (non-Finnish)	0.00316%	31,632

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.Ala92Thr
Coding: c.274G>A
MANE Select: NM_017649
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

renal hypomagnesemia 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypomagnesemia, seizures, and intellectual disability 1

Similar variants

CNNM2 p.Ala92Pro Pathogenic ★ ⚠ 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-ala92thr (accessed [today's date]).

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