Is CCM2 p.Ala295Ser (c.883G>T) pathogenic?

CCM2 p.Ala295Ser (c.883G>T) is classified Uncertain significance in CCM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-02). AlphaMissense: likely benign (0.2611); Absent from gnomAD v4.1.

How common is CCM2 p.Ala295Ser (c.883G>T) in the general population?

CCM2 p.Ala295Ser (c.883G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CCM2 p.Ala295Ser (c.883G>T)?

AlphaMissense predicts likely benign (score 0.2611) — an in-silico prediction, not a clinical call.

CCM2 p.Ala295Ser

c.883G>T · VCV4895980

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2611 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2611	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -6.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 76 kb · p 3.5e-05 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CCM2
Protein: p.Ala295Ser
Coding: c.883G>T
MANE Select: NM_031443
Type: single nucleotide variant
Location: chr7:45073539 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 295: the 'harmonin homology domain' region; an α-helix

Full CCM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCM2 p.Ala295Thr Uncertain significance ★ ⚠ same residue
CCM2 p.Ala295= Likely benign ★ same residue
CCM2 c.289-1G>A Pathogenic/Likely pathogenic ★★ same type
CCM2 c.30+1G>A Pathogenic ★★ same type
CCM2 c.472+1G>C Pathogenic/Likely pathogenic ★★ same type
CCM2 c.473-1G>T Pathogenic ★★ same type
CCM2 c.745+1G>T Pathogenic ★★ same type
CCM2 p.Arg19Ter Pathogenic ★★ 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/ccm2-p-ala295ser (accessed [today's date]).

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