Is CCM2L p.Arg282Trp (c.844C>T) pathogenic?

CCM2L p.Arg282Trp (c.844C>T) is classified Uncertain significance in CCM2L (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-22). AlphaMissense: ambiguous (0.3481); Rare (popmax 0.153%, amr).

How common is CCM2L p.Arg282Trp (c.844C>T) in the general population?

CCM2L p.Arg282Trp (c.844C>T) is rare (popmax 0.153%, amr) (gnomAD).

What do computational predictors say about CCM2L p.Arg282Trp (c.844C>T)?

AlphaMissense predicts ambiguous (score 0.3481) — an in-silico prediction, not a clinical call.

CCM2L p.Arg282Trp

c.844C>T · rs1008181480 · VCV2384989

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3481 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.153%, amr)

Computational evidence

Protein change
AlphaMissense	0.3481	ambiguous
REVEL	0.331	indeterminate
SaProt	LLR -11.62	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -1.3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 21 kb · p 8.3e-05 · regional, not allelic
Overall
CADD	23.6	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 0.153% Admixed American · 48/31,400 alleles

Filtering AF 0.118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.106%

Overall 0.00367% 49/1,333,852 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.153%	654
European (non-Finnish)	9.6e-05%	1,041,748

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.Arg282Trp
Coding: c.844C>T
MANE Select: NM_001365692
dbSNP: rs1008181480
Type: single nucleotide variant
Location: chr20:32019320 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.84
Residue 282: the 'disordered' region

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-arg282trp (accessed [today's date]).

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