Is CCM2 p.Met424Val (c.1270A>G) pathogenic?

CCM2 p.Met424Val (c.1270A>G) is classified Uncertain significance in CCM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: ambiguous (0.4638); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with CCM2 p.Met424Val (c.1270A>G)?

CCM2 p.Met424Val (c.1270A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CCM2 p.Met424Val (c.1270A>G) in the general population?

CCM2 p.Met424Val (c.1270A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CCM2 p.Met424Val (c.1270A>G)?

AlphaMissense predicts ambiguous (score 0.4638) — an in-silico prediction, not a clinical call.

CCM2 p.Met424Val

c.1270A>G · VCV3997520

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4638 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4638	ambiguous
REVEL	0.252	benign-leaning
SaProt	LLR -6.37	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP -2.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 76 kb · p 3.5e-05 · regional, not allelic
Overall
CADD	23.1	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 0.00223% East Asian · 1/44,882 alleles

Overall 0.000137% 2/1,460,820 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
European (non-Finnish)	8.47e-05%	1,180,025

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.Met424Val
Coding: c.1270A>G
MANE Select: NM_031443
Type: single nucleotide variant
Location: chr7:45075992 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 424: 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

Similar variants

CCM2 p.Met424Ile Uncertain significance ★ ⚠ same residue
CCM2 p.Ala186Thr Uncertain significance ★★ ⚠ same condition
CCM2 p.Arg326His Uncertain significance ★★ ⚠ same condition
CCM2 p.Arg423Pro Uncertain significance ★★ ⚠ same condition
CCM2 p.Gln441Arg Uncertain significance ★★ ⚠ same condition
CCM2 p.Ile131Asn Uncertain significance ★★ ⚠ same condition
CCM2 p.Pro102Leu Uncertain significance ★★ ⚠ same condition
CCM2 p.Val374Met Uncertain significance ★★ ⚠ 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-met424val (accessed [today's date]).

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