Is CCM2 p.Phe228fs (c.683_686del) pathogenic?

CCM2 p.Phe228fs (c.683686del) is classified Pathogenic/Likely pathogenic in CCM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-20). Very rare (popmax 8.47e-05%, nfe); Associated with cerebral cavernous malformation 2.

What condition is associated with CCM2 p.Phe228fs (c.683_686del)?

CCM2 p.Phe228fs (c.683_686del) is associated with cerebral cavernous malformation 2 (ClinVar).

How common is CCM2 p.Phe228fs (c.683_686del) in the general population?

CCM2 p.Phe228fs (c.683_686del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

CCM2 p.Phe228fs

c.683_686del · rs1131691538 · VCV429700

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 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	predicted	premature termination codon in exon 6 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.6, 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) · 1/1,180,016 alleles

Overall 0.000137% 2/1,461,868 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)grpmax	8.47e-05%	1,180,016

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe228fs
Coding: c.683_686del
MANE Select: NM_031443
dbSNP: rs1131691538
Type: Deletion
Location: chr7:45069897 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 228: the pid domain; an α-helix

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.Phe228= Likely benign ★★ same residue
CCM2 p.Phe228Cys Uncertain significance ★ ⚠ same residue
CCM2 p.Gln218fs Pathogenic ★★ same condition
CCM2 p.Glu264fs Pathogenic/Likely pathogenic ★★ same condition
CCM2 p.Gly24fs Pathogenic ★★ same condition
CCM2 c.804-12del Benign/Likely benign ★★ same condition
CCM2 p.Ala32fs Pathogenic ★ same condition
CCM2 p.Arg28fs 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-phe228fs (accessed [today's date]).

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