Is CCM2 p.Ser251Pro (c.751T>C) pathogenic?

CCM2 p.Ser251Pro (c.751T>C) is classified Uncertain significance in CCM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: ambiguous (0.4063); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CCM2 p.Ser251Pro (c.751T>C)?

CCM2 p.Ser251Pro (c.751T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CCM2 p.Ser251Pro (c.751T>C) in the general population?

CCM2 p.Ser251Pro (c.751T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CCM2 p.Ser251Pro (c.751T>C)?

AlphaMissense predicts ambiguous (score 0.4063) — an in-silico prediction, not a clinical call.

CCM2 p.Ser251Pro

c.751T>C · VCV4842258

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4063 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4063	ambiguous
REVEL	0.102	moderately benign-leaning
SaProt	LLR -7.91	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 76 kb · p 3.5e-05 · regional, not allelic
Overall
CADD	26.9	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

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.Ser251Pro
Coding: c.751T>C
MANE Select: NM_031443
Type: single nucleotide variant
Location: chr7:45072731 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CCM2 p.Ser251Tyr Uncertain significance ★ ⚠ same residue
CCM2 p.Ala186Thr Uncertain significance ★★ ⚠ same condition
CCM2 p.Arg326His Uncertain significance ★★ ⚠ same condition
CCM2 p.Arg423Pro 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-ser251pro (accessed [today's date]).

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