Is CCN3 p.Cys144Ser (c.431G>C) pathogenic?

CCN3 p.Cys144Ser (c.431G>C) is classified Uncertain significance in CCN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-10). AlphaMissense: likely pathogenic (0.9922); Very rare (popmax 0.00223%, eas).

How common is CCN3 p.Cys144Ser (c.431G>C) in the general population?

CCN3 p.Cys144Ser (c.431G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CCN3 p.Cys144Ser (c.431G>C)?

AlphaMissense predicts likely pathogenic (score 0.9922) — an in-silico prediction, not a clinical call.

CCN3 p.Cys144Ser

c.431G>C · rs1301078897 · VCV3139800

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9922 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9922	likely pathogenic · top 3% in CCN3
REVEL	0.945	strongly pathogenic-leaning
SaProt	LLR -15.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 6,596 bp · p 0.65 · regional, not allelic
Overall
CADD	31.0	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 0.00223% East Asian · 1/44,872 alleles

Overall 6.84e-05% 1/1,461,892 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.Cys144Ser
Coding: c.431G>C
MANE Select: NM_002514
dbSNP: rs1301078897
Type: single nucleotide variant
Location: chr8:119418178 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.88
Residue 144: the vwfc 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-cys144ser (accessed [today's date]).

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