Is CNNM2 p.Val408Ile (c.1222G>A) pathogenic?

CNNM2 p.Val408Ile (c.1222G>A) is classified Uncertain significance in CNNM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-08). AlphaMissense: likely benign (0.2875); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with CNNM2 p.Val408Ile (c.1222G>A)?

CNNM2 p.Val408Ile (c.1222G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CNNM2 p.Val408Ile (c.1222G>A) in the general population?

CNNM2 p.Val408Ile (c.1222G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CNNM2 p.Val408Ile (c.1222G>A)?

AlphaMissense predicts likely benign (score 0.2875) — an in-silico prediction, not a clinical call.

CNNM2 p.Val408Ile

c.1222G>A · VCV4616011

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2875 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2875	likely benign
REVEL	0.398	indeterminate
SaProt	LLR -8.31	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 10	GERP 0.83, phastCons 1
Regional constraint	o/e 0.20	constrained · MANE · 151 bp · p 4.3e-11 · regional, not allelic
Overall
CADD	33.0	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 0.00133% African / African-American · 1/74,930 alleles

Overall 0.000124% 2/1,614,092 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,930
European (non-Finnish)	8.47e-05%	1,180,044

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.Val408Ile
Coding: c.1222G>A
MANE Select: NM_017649
Type: single nucleotide variant
Location: chr10:102919702 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.70 · 7 PDB
Residue 408: 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
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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-val408ile (accessed [today's date]).

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