Is CCM2 p.Leu155Arg (c.464T>G) pathogenic?

CCM2 p.Leu155Arg (c.464T>G) is classified Uncertain significance in CCM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-09). AlphaMissense: likely pathogenic (0.9951); Absent from gnomAD v4.1.

How common is CCM2 p.Leu155Arg (c.464T>G) in the general population?

CCM2 p.Leu155Arg (c.464T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CCM2 p.Leu155Arg (c.464T>G)?

AlphaMissense predicts likely pathogenic (score 0.9951) — an in-silico prediction, not a clinical call.

CCM2 p.Leu155Arg

c.464T>G · rs1562908094 · VCV590659

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9951 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9951	likely pathogenic · top 7% in CCM2
REVEL	0.828	moderately pathogenic-leaning
SaProt	LLR -16.43	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 1.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 76 kb · p 3.5e-05 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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.Leu155Arg
Coding: c.464T>G
MANE Select: NM_031443
dbSNP: rs1562908094
Type: single nucleotide variant
Location: chr7:45064638 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 155: the pid domain; a β-strand

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

Similar variants

CCM2 p.Leu155Pro Uncertain significance ★ ⚠ same residue
CCM2 c.289-1G>A Pathogenic/Likely pathogenic ★★ same type
CCM2 c.30+1G>A Pathogenic ★★ same type
CCM2 c.472+1G>C Pathogenic/Likely pathogenic ★★ same type
CCM2 c.473-1G>T Pathogenic ★★ same type
CCM2 c.745+1G>T Pathogenic ★★ same type
CCM2 p.Arg19Ter Pathogenic ★★ same type
CCM2 p.Arg57Ter Pathogenic/Likely pathogenic ★★ same type

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-leu155arg (accessed [today's date]).

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