Is CCM2 p.Ile428= (c.1284C>T) pathogenic?

CCM2 p.Ile428= (c.1284C>T) is classified Likely benign in CCM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-27). Ultra-rare (popmax 0.0627%, afr); Associated with Inborn genetic diseases.

What condition is associated with CCM2 p.Ile428= (c.1284C>T)?

CCM2 p.Ile428= (c.1284C>T) is associated with Inborn genetic diseases, cerebral cavernous malformation 2 (ClinVar).

How common is CCM2 p.Ile428= (c.1284C>T) in the general population?

CCM2 p.Ile428= (c.1284C>T) is ultra-rare (popmax 0.0627%, afr) (gnomAD).

CCM2 p.Ile428=

c.1284C>T · rs144918172 · VCV590647

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0627%, afr)

Conditions

Inborn genetic diseases

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 4	GERP 0.69, phastCons 1
Overall
CADD	11.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0627% African / African-American · 47/74,918 alleles

Filtering AF 0.0484% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0433%

Overall 0.00322% 52/1,612,970 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0627%	1,594
Admixed American	0.00333%	30,001
Remaining individualsnot grpmax-eligible	0.0032%	31,237
European (non-Finnish)	8.47e-05%	1,180,032

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.Ile428=
Coding: c.1284C>T
MANE Select: NM_031443
dbSNP: rs144918172
Type: single nucleotide variant
Location: chr7:45076006 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 428: an α-helix

Full CCM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cerebral cavernous malformation 2

Similar variants

CCM2 p.Ile428Ser 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-ile428 (accessed [today's date]).

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