Is CCN2 p.Pro295Leu (c.884C>T) pathogenic?

CCN2 p.Pro295Leu (c.884C>T) is classified Uncertain significance in CCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-13). AlphaMissense: likely pathogenic (0.9799); Very rare (popmax 0.00133%, afr).

How common is CCN2 p.Pro295Leu (c.884C>T) in the general population?

CCN2 p.Pro295Leu (c.884C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CCN2 p.Pro295Leu (c.884C>T)?

AlphaMissense predicts likely pathogenic (score 0.9799) — an in-silico prediction, not a clinical call.

CCN2 p.Pro295Leu

c.884C>T · rs1783068231 · VCV2483065

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9799 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9799	likely pathogenic
REVEL	0.614	indeterminate
SaProt	LLR -16.69	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,905 bp · p 0.18 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00133% African / African-American · 1/75,030 alleles

Overall 6.84e-05% 1/1,461,894 alleles · very rare

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: CCN2
Protein: p.Pro295Leu
Coding: c.884C>T
MANE Select: NM_001901
dbSNP: rs1783068231
Type: single nucleotide variant
Location: chr6:131949430 (GRCh38)
Gene constraint: LOEUF 1.05 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.43
Residue 295: a disulfide bond; the ctck domain; the 'heparin-binding' region

Full CCN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCN2 c.290-6C>T Benign ★★ same type
CCN2 c.67-4G>A Likely benign ★★ same type
CCN2 p.Ala101Ser Uncertain significance ★ ⚠ same type
CCN2 p.Ala208Thr Uncertain significance ★ ⚠ same type
CCN2 p.Ala45Val Uncertain significance ★ ⚠ same type
CCN2 p.Ala61Thr Uncertain significance ★ ⚠ same type
CCN2 p.Arg34Gly Uncertain significance ★ ⚠ same type
CCN2 p.Arg42Gly 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/ccn2-p-pro295leu (accessed [today's date]).

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