Is CCM2 p.Arg19Ter (c.55C>T) pathogenic?

CCM2 p.Arg19Ter (c.55C>T) is classified Pathogenic in CCM2 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-05-19). Very rare (popmax 0.00167%, amr); Associated with cerebral cavernous malformation 2.

What condition is associated with CCM2 p.Arg19Ter (c.55C>T)?

CCM2 p.Arg19Ter (c.55C>T) is associated with cerebral cavernous malformation 2 (ClinVar).

How common is CCM2 p.Arg19Ter (c.55C>T) in the general population?

CCM2 p.Arg19Ter (c.55C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

CCM2 p.Arg19Ter

c.55C>T · rs755800734 · VCV447028

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

cerebral cavernous malformation 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 10
Splicing
SpliceAI	Δ0.33	acceptor loss, 24 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 3.8	GERP 0.5, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,002 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,614,006 alleles · very rare exomes 3/1,461,828 · genomes 1/152,178 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,002
South Asian	0.0011%	91,080
European (non-Finnish)	0.000169%	590,023

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.Arg19Ter
Coding: c.55C>T
MANE Select: NM_031443
dbSNP: rs755800734
Type: single nucleotide variant
Location: chr7:45038277 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 19: 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.Arg19= Likely benign ★ same residue
CCM2 c.289-1G>A Pathogenic/Likely pathogenic ★★ same condition
CCM2 c.30+1G>A Pathogenic ★★ same condition
CCM2 c.472+1G>C Pathogenic/Likely pathogenic ★★ same condition
CCM2 c.473-1G>T Pathogenic ★★ same condition
CCM2 c.745+1G>T Pathogenic ★★ same condition
CCM2 p.Arg57Ter Pathogenic/Likely pathogenic ★★ same condition
CCM2 p.Gln107Ter 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-arg19ter (accessed [today's date]).

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