Is CCM2 p.Arg57fs (c.169_172del) pathogenic?

CCM2 p.Arg57fs (c.169172del) is classified Pathogenic in CCM2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2022-04-21). Very rare (popmax 8.47e-05%, nfe); Associated with cerebral cavernous malformation 2.

What condition is associated with CCM2 p.Arg57fs (c.169_172del)?

CCM2 p.Arg57fs (c.169_172del) is associated with cerebral cavernous malformation 2 (ClinVar).

How common is CCM2 p.Arg57fs (c.169_172del) in the general population?

CCM2 p.Arg57fs (c.169_172del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

CCM2 p.Arg57fs

c.169_172del · rs1562882045 · VCV590649

Pathogenic Multiple submitters

Classification

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	predicted	premature termination codon in exon 2 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.4	GERP 1.4, 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) · 1/1,180,026 alleles

Overall 6.84e-05% 1/1,461,840 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.Arg57fs
Coding: c.169_172del
MANE Select: NM_031443
dbSNP: rs1562882045
Type: Microsatellite
Location: chr7:45038386 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 57: a turn

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.Arg57Ter Pathogenic/Likely pathogenic ★★ same residue
CCM2 p.Glu417fs Pathogenic/Likely pathogenic ★★ same condition
CCM2 p.Thr44fs Pathogenic ★ same condition
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-arg57fs (accessed [today's date]).

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