Is CCN2 p.Gly100Ser (c.298G>A) pathogenic?

CCN2 p.Gly100Ser (c.298G>A) is classified Uncertain significance in CCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-25). AlphaMissense: likely benign (0.1642); Very rare (popmax 0.00333%, amr).

How common is CCN2 p.Gly100Ser (c.298G>A) in the general population?

CCN2 p.Gly100Ser (c.298G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CCN2 p.Gly100Ser (c.298G>A)?

AlphaMissense predicts likely benign (score 0.1642) — an in-silico prediction, not a clinical call.

CCN2 p.Gly100Ser

c.298G>A · VCV3487313

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1642 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1642	likely benign
REVEL	0.598	indeterminate
SaProt	LLR -10.16	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,905 bp · p 0.18 · regional, not allelic
Overall
CADD	28.6	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

Grpmax group 0.00333% Admixed American · 2/60,006 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000137% 2/1,460,752 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.Gly100Ser
Coding: c.298G>A
MANE Select: NM_001901
Type: single nucleotide variant
Location: chr6:131950535 (GRCh38)
Gene constraint: LOEUF 1.05 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.43

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

Similar variants

CCN2 p.Gly100Ala Uncertain significance ★ ⚠ same residue
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

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-gly100ser (accessed [today's date]).

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