Is CNNM2 p.Ser489Cys (c.1466C>G) pathogenic?

CNNM2 p.Ser489Cys (c.1466C>G) is classified Uncertain significance in CNNM2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-06-08). AlphaMissense: likely benign (0.0962); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with CNNM2 p.Ser489Cys (c.1466C>G)?

CNNM2 p.Ser489Cys (c.1466C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CNNM2 p.Ser489Cys (c.1466C>G) in the general population?

CNNM2 p.Ser489Cys (c.1466C>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CNNM2 p.Ser489Cys (c.1466C>G)?

AlphaMissense predicts likely benign (score 0.0962) — an in-silico prediction, not a clinical call.

CNNM2 p.Ser489Cys

c.1466C>G · rs775787922 · VCV2052281

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0962 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0962	likely benign
REVEL	0.55	indeterminate
SaProt	LLR -9.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 149 kb · p 1.8e-14 · regional, not allelic
Overall
CADD	27.7	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00124% 20/1,614,088 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.00153%	65,558

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.Ser489Cys
Coding: c.1466C>G
MANE Select: NM_017649
dbSNP: rs775787922
Type: single nucleotide variant
Location: chr10:102919946 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.70 · 7 PDB
Residue 489: the cbs 1 domain; a β-strand

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

NT5C2 p.Thr489= 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.Arg679Cys Uncertain significance ★★ ⚠ same condition
CNNM2 p.Arg679His Uncertain significance ★★ ⚠ same condition
CNNM2 p.Asn657Ser Uncertain significance ★★ ⚠ same condition
CNNM2 p.Asn680Ser 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-ser489cys (accessed [today's date]).

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