Is CCM2 p.Val374Met (c.1120G>A) pathogenic?

CCM2 p.Val374Met (c.1120G>A) is classified Uncertain significance in CCM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-26). AlphaMissense: likely pathogenic (0.9271); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with CCM2 p.Val374Met (c.1120G>A)?

CCM2 p.Val374Met (c.1120G>A) is associated with Inborn genetic diseases, cerebral cavernous malformation 2 (ClinVar).

How common is CCM2 p.Val374Met (c.1120G>A) in the general population?

CCM2 p.Val374Met (c.1120G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CCM2 p.Val374Met (c.1120G>A)?

AlphaMissense predicts likely pathogenic (score 0.9271) — an in-silico prediction, not a clinical call.

CCM2 p.Val374Met

c.1120G>A · rs200669376 · VCV1482493

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9271 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9271	likely pathogenic
REVEL	0.271	benign-leaning
SaProt	LLR -8.14	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP -0.32, 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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00588% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00541%

Overall 0.00552% 89/1,613,646 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.00712%	14,048
Remaining individualsnot grpmax-eligible	0.0032%	31,240
Finnishnot grpmax-eligible	0.00157%	63,616
South Asian	0.0011%	91,092

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.Val374Met
Coding: c.1120G>A
MANE Select: NM_031443
dbSNP: rs200669376
Type: single nucleotide variant
Location: chr7:45075842 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 374: the 'harmonin homology domain' region; a turn

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-val374met (accessed [today's date]).

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