Is CCM2 p.Phe228Cys (c.683T>G) pathogenic?

CCM2 p.Phe228Cys (c.683T>G) is classified Uncertain significance in CCM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-06). AlphaMissense: likely pathogenic (0.9729); Very rare (popmax 8.47e-05%, nfe); Associated with cerebral cavernous malformation 2.

What condition is associated with CCM2 p.Phe228Cys (c.683T>G)?

CCM2 p.Phe228Cys (c.683T>G) is associated with cerebral cavernous malformation 2 (ClinVar).

How common is CCM2 p.Phe228Cys (c.683T>G) in the general population?

CCM2 p.Phe228Cys (c.683T>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CCM2 p.Phe228Cys (c.683T>G)?

AlphaMissense predicts likely pathogenic (score 0.9729) — an in-silico prediction, not a clinical call.

CCM2 p.Phe228Cys

c.683T>G · VCV4279905

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9729 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebral cavernous malformation 2

Computational evidence

Protein change
AlphaMissense	0.9729	likely pathogenic
REVEL	0.269	benign-leaning
SaProt	LLR -5.53	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.45, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 76 kb · p 3.5e-05 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.84e-05% 1/1,461,866 alleles · very rare

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.Phe228Cys
Coding: c.683T>G
MANE Select: NM_031443
Type: single nucleotide variant
Location: chr7:45069899 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 228: the pid domain; 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 p.Phe228= Likely benign ★★ same residue
CCM2 p.Phe228fs Pathogenic/Likely 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

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-phe228cys (accessed [today's date]).

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