Is CNNM2 p.Ala671Val (c.2012C>T) pathogenic?

CNNM2 p.Ala671Val (c.2012C>T) is classified Uncertain significance in CNNM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-23). AlphaMissense: likely benign (0.108); Very rare (popmax 0.00203%, nfe); Associated with renal hypomagnesemia 6.

What condition is associated with CNNM2 p.Ala671Val (c.2012C>T)?

CNNM2 p.Ala671Val (c.2012C>T) is associated with renal hypomagnesemia 6, hypomagnesemia, seizures, and intellectual disability 1 (ClinVar).

How common is CNNM2 p.Ala671Val (c.2012C>T) in the general population?

CNNM2 p.Ala671Val (c.2012C>T) is very rare (popmax 0.00203%, nfe) (gnomAD).

What do computational predictors say about CNNM2 p.Ala671Val (c.2012C>T)?

AlphaMissense predicts likely benign (score 0.108) — an in-silico prediction, not a clinical call.

CNNM2 p.Ala671Val

c.2012C>T · rs375262395 · VCV298646

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.108 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

renal hypomagnesemia 6

Computational evidence

Protein change
AlphaMissense	0.108	likely benign
REVEL	0.339	indeterminate
SaProt	LLR -11.48	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 149 kb · p 1.8e-14 · regional, not allelic
Overall
CADD	25.1	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

Grpmax group 0.00203% European (non-Finnish) · 24/1,179,894 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00155% 25/1,613,828 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00203%	49,162
Remaining individualsnot grpmax-eligible	0.0016%	62,462

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.Ala671Val
Coding: c.2012C>T
MANE Select: NM_017649
dbSNP: rs375262395
Type: single nucleotide variant
Location: chr10:103056903 (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.Ala671Ser Uncertain significance ★ 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.Ala874Thr 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-ala671val (accessed [today's date]).

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