Is CCM2 p.Arg423Pro (c.1268G>C) pathogenic?

CCM2 p.Arg423Pro (c.1268G>C) is classified Uncertain significance in CCM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-20). AlphaMissense: likely pathogenic (0.9685); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with CCM2 p.Arg423Pro (c.1268G>C)?

CCM2 p.Arg423Pro (c.1268G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CCM2 p.Arg423Pro (c.1268G>C) in the general population?

CCM2 p.Arg423Pro (c.1268G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CCM2 p.Arg423Pro (c.1268G>C)?

AlphaMissense predicts likely pathogenic (score 0.9685) — an in-silico prediction, not a clinical call.

CCM2 p.Arg423Pro

c.1268G>C · rs371640199 · VCV2242822

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9685	likely pathogenic
REVEL	0.499	indeterminate
SaProt	LLR -14.96	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 0.64, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 76 kb · p 3.5e-05 · regional, not allelic
Overall
CADD	31.0	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

Grpmax group 0.00133% African / African-American · 1/74,922 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,612,976 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,922
European (non-Finnish)	0.000593%	168,574

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.Arg423Pro
Coding: c.1268G>C
MANE Select: NM_031443
dbSNP: rs371640199
Type: single nucleotide variant
Location: chr7:45075990 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 423: the 'disordered' 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

Similar variants

CCM2 p.Arg423His Uncertain significance ★ ⚠ same residue
CCM2 p.Arg423Cys Uncertain significance ★ ⚠ same residue
CCM2 p.Ala186Thr Uncertain significance ★★ ⚠ same condition
CCM2 p.Arg326His 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-arg423pro (accessed [today's date]).

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