Is CCM2 p.Leu213Pro (c.638T>C) pathogenic?

CCM2 p.Leu213Pro (c.638T>C) is classified Conflicting classifications of pathogenicity in CCM2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-23). AlphaMissense: likely pathogenic (0.9944); Absent from gnomAD v4.1; Associated with cerebral cavernous malformation.

What condition is associated with CCM2 p.Leu213Pro (c.638T>C)?

CCM2 p.Leu213Pro (c.638T>C) is associated with cerebral cavernous malformation, cerebral cavernous malformation 2 (ClinVar).

How common is CCM2 p.Leu213Pro (c.638T>C) in the general population?

CCM2 p.Leu213Pro (c.638T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CCM2 p.Leu213Pro (c.638T>C)?

AlphaMissense predicts likely pathogenic (score 0.9944) — an in-silico prediction, not a clinical call.

CCM2 p.Leu213Pro

c.638T>C · rs1583983649 · VCV655527

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9944 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebral cavernous malformation

Computational evidence

Protein change
AlphaMissense	0.9944	likely pathogenic · top 8% in CCM2
REVEL	0.722	pathogenic-leaning
SaProt	LLR -12.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 76 kb · p 3.5e-05 · regional, not allelic
Overall
CADD	29.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CCM2
Protein: p.Leu213Pro
Coding: c.638T>C
MANE Select: NM_031443
dbSNP: rs1583983649
Type: single nucleotide variant
Location: chr7:45069854 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 213: 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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cerebral cavernous malformation 2

Similar variants

OSM p.Gly213Glu 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-leu213pro (accessed [today's date]).

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