Is CCM2 p.Leu113= (c.339C>T) pathogenic?

CCM2 p.Leu113= (c.339C>T) is classified Benign/Likely benign in CCM2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-14). Rare (popmax 0.231%, sas); Associated with cerebral cavernous malformation 2.

What condition is associated with CCM2 p.Leu113= (c.339C>T)?

CCM2 p.Leu113= (c.339C>T) is associated with cerebral cavernous malformation 2 (ClinVar).

How common is CCM2 p.Leu113= (c.339C>T) in the general population?

CCM2 p.Leu113= (c.339C>T) is rare (popmax 0.231%, sas) (gnomAD).

CCM2 p.Leu113=

c.339C>T · rs146259619 · VCV698108

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.231%, sas)

Conditions

cerebral cavernous malformation 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.59, phastCons 1
Overall
CADD	9.674	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.231% South Asian · 210/91,038 alleles

Filtering AF 0.205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.195%

Overall 0.0338% 546/1,613,820 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.231%	434
Middle Eastern	0.203%	492
African / African-American	0.0493%	2,028
Remaining individualsnot grpmax-eligible	0.0432%	2,314
European (non-Finnish)	0.0214%	4,682
Admixed American	0.01%	10,003
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
Finnishnot grpmax-eligible	0.00156%	64,012

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.Leu113=
Coding: c.339C>T
MANE Select: NM_031443
dbSNP: rs146259619
Type: single nucleotide variant
Location: chr7:45064513 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 113: the pid domain; a β-strand

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.Leu113Pro Pathogenic ★ 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.Arg19Ter Pathogenic ★★ same condition
CCM2 p.Arg57Ter Pathogenic/Likely 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-leu113 (accessed [today's date]).

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