Is CNNM2 p.Pro505= (c.1515C>T) pathogenic?

CNNM2 p.Pro505= (c.1515C>T) is classified Benign/Likely benign in CNNM2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-05-05). Ultra-rare (popmax 0.0625%, nfe); Associated with renal hypomagnesemia 6.

What condition is associated with CNNM2 p.Pro505= (c.1515C>T)?

CNNM2 p.Pro505= (c.1515C>T) is associated with renal hypomagnesemia 6 (ClinVar).

How common is CNNM2 p.Pro505= (c.1515C>T) in the general population?

CNNM2 p.Pro505= (c.1515C>T) is ultra-rare (popmax 0.0625%, nfe) (gnomAD).

CNNM2 p.Pro505=

c.1515C>T · rs144140948 · VCV298642

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0625%, nfe)

Conditions

renal hypomagnesemia 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.3	GERP -4
Overall
CADD	3.548	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0625% European (non-Finnish) · 738/1,180,052 alleles

Filtering AF 0.0588% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0573%

Overall 0.047% 759/1,614,096 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0625%	1,599
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,401
Finnishnot grpmax-eligible	0.0125%	8,004
Remaining individualsnot grpmax-eligible	0.008%	12,498
African / African-American	0.00534%	18,732

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.Pro505=
Coding: c.1515C>T
MANE Select: NM_017649
dbSNP: rs144140948
Type: single nucleotide variant
Location: chr10:102919995 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.70 · 7 PDB
Residue 505: the cbs 1 domain; an α-helix

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

Similar variants

CNNM2 p.Arg602Ter 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
CNNM2 p.Ala92Thr Uncertain significance ★★ ⚠ same condition
CNNM2 p.Arg153His Uncertain significance ★★ ⚠ same condition
CNNM2 p.Arg30Cys 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-pro505 (accessed [today's date]).

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