Is CCM2 p.Arg412Trp (c.1234C>T) pathogenic?

CCM2 p.Arg412Trp (c.1234C>T) is classified Uncertain significance in CCM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-11). AlphaMissense: likely benign (0.0884); Very rare (popmax 0.00551%, nfe); Associated with cerebral cavernous malformation 2.

What condition is associated with CCM2 p.Arg412Trp (c.1234C>T)?

CCM2 p.Arg412Trp (c.1234C>T) is associated with cerebral cavernous malformation 2, vasculitis (ClinVar).

How common is CCM2 p.Arg412Trp (c.1234C>T) in the general population?

CCM2 p.Arg412Trp (c.1234C>T) is very rare (popmax 0.00551%, nfe) (gnomAD).

What do computational predictors say about CCM2 p.Arg412Trp (c.1234C>T)?

AlphaMissense predicts likely benign (score 0.0884) — an in-silico prediction, not a clinical call.

CCM2 p.Arg412Trp

c.1234C>T · rs544276945 · VCV523540

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0884 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00551%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebral cavernous malformation 2

Computational evidence

Protein change
AlphaMissense	0.0884	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -8.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -0.68, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 76 kb · p 3.5e-05 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00551% European (non-Finnish) · 65/1,180,008 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00403%

Overall 0.0044% 71/1,613,136 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00551%	18,154
East Asian	0.00446%	22,441
African / African-American	0.00267%	37,518
Remaining individualsnot grpmax-eligible	0.0016%	62,502
South Asian	0.0011%	91,074

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.Arg412Trp
Coding: c.1234C>T
MANE Select: NM_031443
dbSNP: rs544276945
Type: single nucleotide variant
Location: chr7:45075956 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 412: the 'disordered' region

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

Also linked: vasculitis

Similar variants

CCM2 p.Arg412fs Pathogenic/Likely pathogenic ★★ same residue
CCM2 p.Arg412Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg412trp (accessed [today's date]).

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