Is CCM2 p.Met1Ile (c.3G>A) pathogenic?

CCM2 p.Met1Ile (c.3G>A) is classified Conflicting classifications of pathogenicity in CCM2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-06-30). Absent from gnomAD v4.1; Associated with CCM2-related disorder.

What condition is associated with CCM2 p.Met1Ile (c.3G>A)?

CCM2 p.Met1Ile (c.3G>A) is associated with CCM2-related disorder (ClinVar).

How common is CCM2 p.Met1Ile (c.3G>A) in the general population?

CCM2 p.Met1Ile (c.3G>A) is absent from gnomAD v4.1 (gnomAD).

CCM2 p.Met1Ile

c.3G>A · VCV3337891

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,294,548)

Conditions

CCM2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.227	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 0.49, phastCons 1
Overall
CADD	23.7	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

No allele count reported in gnomAD v4.1 (AN 1,294,548). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CCM2
Protein: p.Met1Ile
Coding: c.3G>A
MANE Select: NM_031443
Type: single nucleotide variant
Location: chr7:45000336 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 1: the 'disordered' region

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

Disease context

CCM2-related disorder

Similar variants

CCM2 p.Met1Val Pathogenic ★★ same residue
CCM2 p.Gln107Ter Pathogenic ★★ same condition
CCM2 p.Lys360Ter Pathogenic/Likely pathogenic ★★ same condition
CCM2 c.205-2A>G Likely pathogenic ★ same condition
CCM2 c.31-3C>A Uncertain significance ★ same condition
CCM2 p.Glu54Ter Likely pathogenic same condition
CCM2 p.Ala140Thr Uncertain significance ⚠ same condition
CCM2 c.915+10C>T Likely benign 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-met1ile (accessed [today's date]).

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