Is CNNM2 p.Val290Leu (c.868G>C) pathogenic?

CNNM2 p.Val290Leu (c.868G>C) is classified Uncertain significance in CNNM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-26). AlphaMissense: likely pathogenic (0.8887); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CNNM2 p.Val290Leu (c.868G>C)?

CNNM2 p.Val290Leu (c.868G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CNNM2 p.Val290Leu (c.868G>C) in the general population?

CNNM2 p.Val290Leu (c.868G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNNM2 p.Val290Leu (c.868G>C)?

AlphaMissense predicts likely pathogenic (score 0.8887) — an in-silico prediction, not a clinical call.

CNNM2 p.Val290Leu

c.868G>C · VCV3268172

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8887 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8887	likely pathogenic
REVEL	0.524	indeterminate
SaProt	LLR -8.36	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 0.66, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 412 bp · p 2.8e-23 · regional, not allelic
Overall
CADD	28.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CNNM2
Protein: p.Val290Leu
Coding: c.868G>C
MANE Select: NM_017649
Type: single nucleotide variant
Location: chr10:102919348 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.70 · 7 PDB
Residue 290: the cnnm transmembrane domain

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.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
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-val290leu (accessed [today's date]).

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