Is CCM2 p.Ala117= (c.351G>A) pathogenic?

CCM2 p.Ala117= (c.351G>A) is classified Benign in CCM2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-19). Common (popmax 13.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with cerebral cavernous malformation 2.

What condition is associated with CCM2 p.Ala117= (c.351G>A)?

CCM2 p.Ala117= (c.351G>A) is associated with cerebral cavernous malformation 2 (ClinVar).

CCM2 p.Ala117=

Q: How common is CCM2 p.Ala117= (c.351G>A) in the general population?

CCM2 p.Ala117= (c.351G>A) is common (popmax 13.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.351G>A · rs35888291 · VCV261970

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 13.4%, afr) — too common for a highly-penetrant pathogenic allele

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 0.03	GERP -3.5, phastCons 0.82
Overall
CADD	12.72	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13.4% African / African-American · 10,046/74,974 alleles

Filtering AF 13.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 13.1%

Overall 0.724% 11,677/1,613,824 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	13.4%	7
Admixed American	1.06%	94
Remaining individualsnot grpmax-eligible	1.01%	99
Middle Eastern	0.403%	248
South Asian	0.0395%	2,529
European (non-Finnish)	0.0255%	3,920
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602

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.Ala117=
Coding: c.351G>A
MANE Select: NM_031443
dbSNP: rs35888291
Type: single nucleotide variant
Location: chr7:45064525 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 117: 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.Ala117Val Uncertain significance ★ ⚠ 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-ala117 (accessed [today's date]).

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