Is CCN2 p.Arg22Pro (c.65G>C) pathogenic?

CCN2 p.Arg22Pro (c.65G>C) is classified Pathogenic in CCN2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-06-04). AlphaMissense: likely benign (0.0737); Absent from gnomAD v4.1; Associated with spondyloepimetaphyseal dysplasia, Li-Shao-Li type.

What condition is associated with CCN2 p.Arg22Pro (c.65G>C)?

CCN2 p.Arg22Pro (c.65G>C) is associated with spondyloepimetaphyseal dysplasia, Li-Shao-Li type (ClinVar).

How common is CCN2 p.Arg22Pro (c.65G>C) in the general population?

CCN2 p.Arg22Pro (c.65G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CCN2 p.Arg22Pro (c.65G>C)?

AlphaMissense predicts likely benign (score 0.0737) — an in-silico prediction, not a clinical call.

CCN2 p.Arg22Pro

c.65G>C · VCV3629449

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0737 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,332,040)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spondyloepimetaphyseal dysplasia, Li-Shao-Li type

Computational evidence

Protein change
AlphaMissense	0.0737	likely benign ⚠ discordant with ClinVar
REVEL	0.245	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 -0.29	GERP -1, phastCons 0.2
Regional constraint	o/e 0.94	unconstrained · MANE · 1,905 bp · p 0.18 · regional, not allelic
Overall
CADD	17.66	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

No allele count reported in gnomAD v4.1 (AN 1,332,040). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CCN2
Protein: p.Arg22Pro
Coding: c.65G>C
MANE Select: NM_001901
Type: single nucleotide variant
Location: chr6:131951108 (GRCh38)
Gene constraint: LOEUF 1.05 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.43
Residue 22: a UniProt-annotated variant site (in semdlsl; likely pathogenic; decreased ccn2 protein secretion)

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

Disease context

spondyloepimetaphyseal dysplasia, Li-Shao-Li type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-arg22pro (accessed [today's date]).

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