Is CCM2 p.Thr305= (c.915G>A) pathogenic?

CCM2 p.Thr305= (c.915G>A) is classified Benign in CCM2 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-03). Common (popmax 32.2%, amr) — too common for a highly-penetrant pathogenic allele; Associated with cerebral cavernous malformation 2.

What condition is associated with CCM2 p.Thr305= (c.915G>A)?

CCM2 p.Thr305= (c.915G>A) is associated with cerebral cavernous malformation 2 (ClinVar).

CCM2 p.Thr305=

Q: How common is CCM2 p.Thr305= (c.915G>A) in the general population?

CCM2 p.Thr305= (c.915G>A) is common (popmax 32.2%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.915G>A · rs2289367 · VCV261975

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 32.2%, amr) — 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
Pangolin	Δ0.24	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 1.8	GERP -3.2, phastCons 1
Overall
CADD	18.71	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 32.2% Admixed American · 19,213/59,706 alleles

Filtering AF 31.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 31.6%

Overall 21.8% 349,323/1,602,280 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	32.2%	3
African / African-American	25.5%	4
South Asian	21.6%	5
European (non-Finnish)	21.4%	5
Remaining individualsnot grpmax-eligible	20.7%	5
Finnishnot grpmax-eligible	20.5%	5
Ashkenazi Jewishnot grpmax-eligible	18%	6
Middle Eastern	18%	6
East Asian	17.9%	6
Amishnot grpmax-eligible	16.8%	6

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.Thr305=
Coding: c.915G>A
MANE Select: NM_031443
dbSNP: rs2289367
Type: single nucleotide variant
Location: chr7:45073571 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 305: the 'harmonin homology domain' region; 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 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
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-thr305 (accessed [today's date]).

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