Is CNNM2 p.Ser614= (c.1842T>C) pathogenic?

CNNM2 p.Ser614= (c.1842T>C) is classified Benign in CNNM2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-05-05). Common (popmax 50.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with hypomagnesemia, seizures, and intellectual disability 1.

CNNM2 p.Ser614=

Q: What condition is associated with CNNM2 p.Ser614= (c.1842T>C)?

CNNM2 p.Ser614= (c.1842T>C) is associated with hypomagnesemia, seizures, and intellectual disability 1, renal hypomagnesemia 6 (ClinVar).

Q: How common is CNNM2 p.Ser614= (c.1842T>C) in the general population?

CNNM2 p.Ser614= (c.1842T>C) is common (popmax 50.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1842T>C · rs2275271 · VCV298645

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 50.9%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

hypomagnesemia, seizures, and intellectual disability 1

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 -1.6	GERP -4.4
Overall
CADD	8.155	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 50.9% East Asian · 22,830/44,846 alleles

Filtering AF 50.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 50.1%

Overall 40.2% 648,863/1,613,048 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	50.9%	2
Middle Eastern	43.9%	2
Ashkenazi Jewishnot grpmax-eligible	42.4%	2
South Asian	42.2%	2
Admixed American	41.5%	2
Remaining individualsnot grpmax-eligible	41.1%	2
European (non-Finnish)	39.8%	3
African / African-American	37.6%	3
Finnishnot grpmax-eligible	37.2%	3
Amishnot grpmax-eligible	34.9%	3

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.Ser614=
Coding: c.1842T>C
MANE Select: NM_017649
dbSNP: rs2275271
Type: single nucleotide variant
Location: chr10:103054405 (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.Ser614_Glu615delinsArg 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
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-ser614 (accessed [today's date]).

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