Is CCM2L p.Arg442Gln (c.1325G>A) pathogenic?

CCM2L p.Arg442Gln (c.1325G>A) is classified Uncertain significance in CCM2L (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-19). AlphaMissense: ambiguous (0.5264); Very rare (popmax 0.00401%, afr).

How common is CCM2L p.Arg442Gln (c.1325G>A) in the general population?

CCM2L p.Arg442Gln (c.1325G>A) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about CCM2L p.Arg442Gln (c.1325G>A)?

AlphaMissense predicts ambiguous (score 0.5264) — an in-silico prediction, not a clinical call.

CCM2L p.Arg442Gln

c.1325G>A · rs774474624 · VCV2348561

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5264 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Computational evidence

Protein change
AlphaMissense	0.5264	ambiguous
REVEL	0.395	indeterminate
SaProt	LLR -10.42	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 21 kb · p 8.3e-05 · regional, not allelic
Overall
CADD	25.9	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 0.00401% African / African-American · 3/74,852 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000868% 14/1,613,408 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,819
African / African-Americangrpmax	0.00401%	24,951
Admixed American	0.00334%	29,961
South Asian	0.0033%	30,349
East Asian	0.00223%	44,850
European (non-Finnish)	0.00017%	589,859

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CCM2L
Protein: p.Arg442Gln
Coding: c.1325G>A
MANE Select: NM_001365692
dbSNP: rs774474624
Type: single nucleotide variant
Location: chr20:32029761 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.84

Full CCM2L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCM2L p.Ala183Glu Uncertain significance ★ ⚠ same type
CCM2L p.Ala214Gly Uncertain significance ★ ⚠ same type
CCM2L p.Ala299Ser Uncertain significance ★ ⚠ same type
CCM2L p.Ala435= Uncertain significance ★ same type
CCM2L p.Ala93Ser Uncertain significance ★ ⚠ same type
CCM2L p.Arg195Cys Uncertain significance ★ ⚠ same type
CCM2L p.Arg204Gln Uncertain significance ★ ⚠ same type
CCM2L p.Arg215Trp Uncertain significance ★ ⚠ same type

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/ccm2l-p-arg442gln (accessed [today's date]).

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