Is CCN3 p.Arg227Trp (c.679C>T) pathogenic?

CCN3 p.Arg227Trp (c.679C>T) is classified Uncertain significance in CCN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-05). AlphaMissense: likely pathogenic (0.9292); Ultra-rare (popmax 0.0164%, mid).

How common is CCN3 p.Arg227Trp (c.679C>T) in the general population?

CCN3 p.Arg227Trp (c.679C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CCN3 p.Arg227Trp (c.679C>T)?

AlphaMissense predicts likely pathogenic (score 0.9292) — an in-silico prediction, not a clinical call.

CCN3 p.Arg227Trp

c.679C>T · VCV3487315

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9292 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9292	likely pathogenic
REVEL	0.836	moderately pathogenic-leaning
SaProt	LLR -12.94	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 2.2	GERP 0.004, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 6,596 bp · p 0.65 · regional, not allelic
Overall
CADD	26.5	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000496% 8/1,614,074 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00445%	22,447
South Asian	0.0022%	45,540
European (non-Finnish)	0.000254%	393,348

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.Arg227Trp
Coding: c.679C>T
MANE Select: NM_002514
Type: single nucleotide variant
Location: chr8:119419247 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.88
Residue 227: the tsp type-1 domain

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

Similar variants

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CCN3 p.Ala51Ser Uncertain significance ★ ⚠ same type
CCN3 p.Arg143His Uncertain significance ★ ⚠ same type
CCN3 p.Arg233Cys Uncertain significance ★ ⚠ same type
CCN3 p.Arg299His Uncertain significance ★ ⚠ same type
CCN3 p.Arg34Pro 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-arg227trp (accessed [today's date]).

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