Is CCM2 p.Arg412fs (c.1234dup) pathogenic?

CCM2 p.Arg412fs (c.1234dup) is classified Pathogenic/Likely pathogenic in CCM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-28). Very rare (popmax 8.47e-05%, nfe); Associated with cerebral cavernous malformation 2.

What condition is associated with CCM2 p.Arg412fs (c.1234dup)?

CCM2 p.Arg412fs (c.1234dup) is associated with cerebral cavernous malformation 2 (ClinVar).

How common is CCM2 p.Arg412fs (c.1234dup) in the general population?

CCM2 p.Arg412fs (c.1234dup) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

CCM2 p.Arg412fs

c.1234dup · rs1331484727 · VCV590645

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

cerebral cavernous malformation 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (10 of 10) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.2	GERP -0.34, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,008 alleles

Overall 6.85e-05% 1/1,460,862 alleles · very rare

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: CCM2
Protein: p.Arg412fs
Coding: c.1234dup
MANE Select: NM_031443
dbSNP: rs1331484727
Type: Duplication
Location: chr7:45075954 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 412: the 'disordered' region

Full CCM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cerebral cavernous malformation 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CCM2 p.Arg412Trp Uncertain significance ★★ ⚠ same residue
CCM2 p.Glu359delinsProTer Pathogenic ★ same condition
CCM2 p.His104fs Pathogenic ★ same condition
CCM2 p.Pro77fs Pathogenic ★ same condition
CCM2 p.Trp124fs Pathogenic ★ same condition
CCM2 p.Val67fs Pathogenic ★ same condition
CCM2 c.204+2dup Uncertain significance ★ same condition
CCM2 p.Arg412Gln Conflicting classifications of pathogenicity ★ ⚠ same residue

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/ccm2-p-arg412fs (accessed [today's date]).

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