Is CCM2 p.Arg354Lys (c.1061G>A) pathogenic?

CCM2 p.Arg354Lys (c.1061G>A) is classified Conflicting classifications of pathogenicity in CCM2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-24). AlphaMissense: likely pathogenic (0.9425); Ultra-rare (popmax 0.0286%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CCM2 p.Arg354Lys (c.1061G>A)?

CCM2 p.Arg354Lys (c.1061G>A) is associated with Inborn genetic diseases, cerebral cavernous malformation 2 (ClinVar).

How common is CCM2 p.Arg354Lys (c.1061G>A) in the general population?

CCM2 p.Arg354Lys (c.1061G>A) is ultra-rare (popmax 0.0286%, nfe) (gnomAD).

What do computational predictors say about CCM2 p.Arg354Lys (c.1061G>A)?

AlphaMissense predicts likely pathogenic (score 0.9425) — an in-silico prediction, not a clinical call.

CCM2 p.Arg354Lys

c.1061G>A · rs145579135 · VCV995333

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9425 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0286%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9425	likely pathogenic
REVEL	0.304	indeterminate
SaProt	LLR -4.50	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.81, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 76 kb · p 3.5e-05 · regional, not allelic
Overall
CADD	25.6	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 0.0286% European (non-Finnish) · 337/1,180,026 alleles

Filtering AF 0.026% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.025%

Overall 0.0225% 363/1,613,542 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0286%	3,502
Remaining individualsnot grpmax-eligible	0.024%	4,165
African / African-American	0.012%	8,322
Finnishnot grpmax-eligible	0.00157%	63,572
South Asian	0.0011%	91,084

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.Arg354Lys
Coding: c.1061G>A
MANE Select: NM_031443
dbSNP: rs145579135
Type: single nucleotide variant
Location: chr7:45075783 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 354: the 'harmonin homology domain' region; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cerebral cavernous malformation 2

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-arg354lys (accessed [today's date]).

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