Is CCM2 p.Pro271Thr (c.811C>A) pathogenic?

CCM2 p.Pro271Thr (c.811C>A) is classified Uncertain significance in CCM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-20). AlphaMissense: likely benign (0.0749); Very rare (popmax 0.00254%, nfe).

How common is CCM2 p.Pro271Thr (c.811C>A) in the general population?

CCM2 p.Pro271Thr (c.811C>A) is very rare (popmax 0.00254%, nfe) (gnomAD).

What do computational predictors say about CCM2 p.Pro271Thr (c.811C>A)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

CCM2 p.Pro271Thr

c.811C>A · rs755763949 · VCV2573788

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.33	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 0.88	GERP 0.52, phastCons 0.46
Regional constraint	o/e 0.83	unconstrained · MANE · 76 kb · p 3.5e-05 · regional, not allelic
Overall
CADD	16.42	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

Grpmax group 0.00254% European (non-Finnish) · 30/1,179,778 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00192% 31/1,613,220 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00254%	39,326
Finnishnot grpmax-eligible	0.00158%	63,458

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.Pro271Thr
Coding: c.811C>A
MANE Select: NM_031443
dbSNP: rs755763949
Type: single nucleotide variant
Location: chr7:45073467 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB

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

Similar variants

CCM2 p.Pro271Leu Uncertain significance ★ ⚠ 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
CCM2 p.Arg57Ter Pathogenic/Likely 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-pro271thr (accessed [today's date]).

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