Is CCM2 p.Lys309Arg (c.926A>G) pathogenic?

CCM2 p.Lys309Arg (c.926A>G) is classified Benign in CCM2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-04-30). AlphaMissense: likely benign (0.3024); Rare (popmax 0.195%, sas); Associated with cerebral cavernous malformation 2.

What condition is associated with CCM2 p.Lys309Arg (c.926A>G)?

CCM2 p.Lys309Arg (c.926A>G) is associated with cerebral cavernous malformation 2 (ClinVar).

How common is CCM2 p.Lys309Arg (c.926A>G) in the general population?

CCM2 p.Lys309Arg (c.926A>G) is rare (popmax 0.195%, sas) (gnomAD).

What do computational predictors say about CCM2 p.Lys309Arg (c.926A>G)?

AlphaMissense predicts likely benign (score 0.3024) — an in-silico prediction, not a clinical call.

CCM2 p.Lys309Arg

c.926A>G · rs535112809 · VCV2172985

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3024 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.195%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebral cavernous malformation 2

Computational evidence

Protein change
AlphaMissense	0.3024	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -8.52	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 76 kb · p 3.5e-05 · regional, not allelic
Overall
CADD	25.2	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 0.195% South Asian · 178/91,086 alleles

Filtering AF 0.172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.163%

Overall 0.0146% 236/1,613,642 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.195%	512
Ashkenazi Jewishnot grpmax-eligible	0.0439%	2,278
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0256%	3,906
Admixed American	0.0117%	8,575
European (non-Finnish)	0.00169%	59,002

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.Lys309Arg
Coding: c.926A>G
MANE Select: NM_031443
dbSNP: rs535112809
Type: single nucleotide variant
Location: chr7:45074280 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 309: the 'harmonin homology domain' region; a turn

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 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
CCM2 p.Gln107Ter 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-lys309arg (accessed [today's date]).

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