Is CNNM2 p.Arg679Cys (c.2035C>T) pathogenic?

CNNM2 p.Arg679Cys (c.2035C>T) is classified Uncertain significance in CNNM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-07). AlphaMissense: ambiguous (0.3744); Ultra-rare (popmax 0.0134%, afr); Associated with Inborn genetic diseases.

What condition is associated with CNNM2 p.Arg679Cys (c.2035C>T)?

CNNM2 p.Arg679Cys (c.2035C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CNNM2 p.Arg679Cys (c.2035C>T) in the general population?

CNNM2 p.Arg679Cys (c.2035C>T) is ultra-rare (popmax 0.0134%, afr) (gnomAD).

What do computational predictors say about CNNM2 p.Arg679Cys (c.2035C>T)?

AlphaMissense predicts ambiguous (score 0.3744) — an in-silico prediction, not a clinical call.

CNNM2 p.Arg679Cys

c.2035C>T · rs200419339 · VCV2463656

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3744 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3744	ambiguous
REVEL	0.632	indeterminate
SaProt	LLR -12.28	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.9, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 149 kb · p 1.8e-14 · regional, not allelic
Overall
CADD	32.0	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 0.0134% African / African-American · 10/74,868 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00211% 34/1,613,334 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0134%	7,487
Remaining individualsnot grpmax-eligible	0.00801%	12,487
East Asian	0.00668%	14,962
South Asian	0.0044%	22,741
European (non-Finnish)	0.00102%	98,314

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.Arg679Cys
Coding: c.2035C>T
MANE Select: NM_017649
dbSNP: rs200419339
Type: single nucleotide variant
Location: chr10:103056926 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNNM2 p.Arg679His Uncertain significance ★★ ⚠ same residue
CNNM2 p.Arg679= Likely benign ★ same residue
CNNM2 p.Ala45Ser Uncertain significance ★★ ⚠ same condition
CNNM2 p.Arg153His Uncertain significance ★★ ⚠ same condition
CNNM2 p.Arg30Cys Uncertain significance ★★ ⚠ same condition
CNNM2 p.Asn657Ser Uncertain significance ★★ ⚠ same condition
CNNM2 p.Asn680Ser Uncertain significance ★★ ⚠ same condition
CNNM2 p.Gln826Pro 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-arg679cys (accessed [today's date]).

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