Is CCN3 p.Pro40Ser (c.118C>T) pathogenic?

CCN3 p.Pro40Ser (c.118C>T) is classified Uncertain significance in CCN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-10). AlphaMissense: likely benign (0.0784); Very rare (popmax 0.00393%, nfe).

How common is CCN3 p.Pro40Ser (c.118C>T) in the general population?

CCN3 p.Pro40Ser (c.118C>T) is very rare (popmax 0.00393%, nfe) (gnomAD).

What do computational predictors say about CCN3 p.Pro40Ser (c.118C>T)?

AlphaMissense predicts likely benign (score 0.0784) — an in-silico prediction, not a clinical call.

CCN3 p.Pro40Ser

c.118C>T · VCV3487317

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0784 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00393%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0784	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -4.85	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 4.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 6,596 bp · p 0.65 · regional, not allelic
Overall
CADD	23.9	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 0.00393% European (non-Finnish) · 46/1,170,918 alleles

Filtering AF 0.00301% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00269%

Overall 0.00301% 48/1,595,272 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00393%	25,455
Remaining individualsnot grpmax-eligible	0.00324%	30,848

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.Pro40Ser
Coding: c.118C>T
MANE Select: NM_002514
Type: single nucleotide variant
Location: chr8:119416777 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.88
Residue 40: 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-pro40ser (accessed [today's date]).

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