Is CCM2 p.Glu417fs (c.1250_1251del) pathogenic?

CCM2 p.Glu417fs (c.12501251del) is classified Pathogenic/Likely pathogenic in CCM2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-11-27). Very rare (popmax 8.47e-05%, nfe); Associated with cerebral cavernous malformation 2.

What condition is associated with CCM2 p.Glu417fs (c.1250_1251del)?

CCM2 p.Glu417fs (c.1250_1251del) is associated with cerebral cavernous malformation 2 (ClinVar).

How common is CCM2 p.Glu417fs (c.1250_1251del) in the general population?

CCM2 p.Glu417fs (c.1250_1251del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

CCM2 p.Glu417fs

c.1250_1251del · rs1562921605 · VCV585627

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 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 5.9	GERP 0.68, 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) · 1/1,180,028 alleles

Overall 6.85e-05% 1/1,460,864 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.Glu417fs
Coding: c.1250_1251del
MANE Select: NM_031443
dbSNP: rs1562921605
Type: Microsatellite
Location: chr7:45075970 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 417: 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.Arg57fs Pathogenic ★★ same condition
CCM2 p.Thr44fs Pathogenic ★ same condition
CCM2 p.Glu417Gly Uncertain significance ★ ⚠ same residue
CCM2 c.289-1G>A Pathogenic/Likely pathogenic ★★ same condition
CCM2 c.30+1G>A Pathogenic ★★ same condition
CCM2 c.30+5_30+6delinsTT Pathogenic/Likely pathogenic ★★ same condition
CCM2 c.472+1G>C Pathogenic/Likely pathogenic ★★ same condition
CCM2 c.473-1G>T Pathogenic ★★ 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/ccm2-p-glu417fs (accessed [today's date]).

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