Is CCN3 p.Ile101Val (c.301A>G) pathogenic?

CCN3 p.Ile101Val (c.301A>G) is classified Uncertain significance in CCN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-12). AlphaMissense: likely benign (0.1853); Very rare (popmax 0.00136%, nfe).

How common is CCN3 p.Ile101Val (c.301A>G) in the general population?

CCN3 p.Ile101Val (c.301A>G) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about CCN3 p.Ile101Val (c.301A>G)?

AlphaMissense predicts likely benign (score 0.1853) — an in-silico prediction, not a clinical call.

CCN3 p.Ile101Val

c.301A>G · VCV4221990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1853 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1853	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -6.57	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 5.7	GERP -0.66, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 6,596 bp · p 0.65 · regional, not allelic
Overall
CADD	16.01	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 0.00136% European (non-Finnish) · 16/1,178,648 alleles

Filtering AF 0.000804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.000993% 16/1,611,956 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: CCN3
Protein: p.Ile101Val
Coding: c.301A>G
MANE Select: NM_002514
Type: single nucleotide variant
Location: chr8:119416960 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.88
Residue 101: a disulfide bond; the igfbp n-terminal domain

Full CCN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCN3 p.Cys15Phe Benign ★★ same type
CCN3 p.Ala157Asp Uncertain significance ★ ⚠ same type
CCN3 p.Ala187Ser Uncertain significance ★ ⚠ same type
CCN3 p.Ala51Ser Uncertain significance ★ ⚠ same type
CCN3 p.Arg143His Uncertain significance ★ ⚠ same type
CCN3 p.Arg227Trp Uncertain significance ★ ⚠ same type
CCN3 p.Arg233Cys Uncertain significance ★ ⚠ same type
CCN3 p.Arg299His 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/ccn3-p-ile101val (accessed [today's date]).

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